CALL TO ORDER

Panel Chair Kenneth L. Noller, M.D., called the meeting to order at 9:00 a.m. and asked the panel members to introduce themselves. Panel Executive Secretary Michael T. Bailey, Ph.D., announced there would be no OB/GYN Devices Panel on August 15 and 16, 2005; the remaining panel meeting dates for this year are November 15 and 16, 2005. He then read into the record the appointment of seven temporary voting members: Marcelle I. Cedars, M.D.; Ralph B. D’Agostino, Ph.D.; Gary S. Eglinton, M.D.; Jay D. Iams, M.D.; Julian T. Parer, M.D., Ph.D.; Susan M. Ramin, M.D.; and Deborah A.Wing, M.D. Dr. Bailey then read the conflict of interest statement. The Agency had no conflicts to report.

Sousan S. Altaie, Ph.D., Scientific Policy Advisor, Office of In Vitro Diagnostic Device Evaluation and Safety, gave a presentation on FDA’s Critical Path Initiative, an effort to make product development more predictable and less costly. Critical path tools are used in the assessment of safety to predict whether the product will be harmful; in proof of efficacy to determine if it will have medical benefits; and in industrialization to ensure the product is manufactured with consistent quality.

Colin Pollard, Chief, Obstetrics and Gynecology Devices Branch, welcomed the panel and noted that they would be looking at a pre-market approval application (PMA P020001) from Neoventa Medical AB for the STAN^®S31,a fetal heart monitoring system. The Panel first looked at this system in April of 2002 in a PMA based on a large Swedish randomized control trial (RCT) that showed positive benefit in reducing metabolic acidosis and operative deliveries. However, the Panel voted 6-5 not to approve the device because all of the clinical data came from Sweden and there were concerns about how the technology would transfer to the U.S. The FDA in June of 2003 went to the company with plans for bridging studies to examine how U.S. clinicians learned and used the technology.

OPEN PUBLIC HEARING

No public comments were made. Dr. Bailey read into the record a written statement from the American College of Obstetricians and Gynecologists (ACOG) Office of the Deputy Executive Vice President and Vice President of Practice Activities.

ACOG’s Committee on Obstetric Practice cannot endorse the STAN PMA because of limited evidence the technology improves maternal-fetal outcomes. The Committee is also concerned about the need to monitor clinical training of the device. The Committee feels that if the PMA is approved, post-marketing surveillance of all monitored cases will require short-term neonatal outcome variables, including paired (artery and vein) umbilical blood gas analysis.

NEOVENTA MEDICAL AB PRESENTATION: P020001

Marie Marlow, President and CEO, M Squared Associates, began the sponsor’s presentation by presenting the history of the PMA process for the STAN^®device. She then introduced the other sponsor presenters as well as additional individuals available to help answer questions.

Lawrence D. Devoe, M.D., Chairperson, Department of Obstetrics and Gynecology, Medical College of Georgia, began with a discussion of the current practice of electronic fetal monitoring (EFM) in the U.S. The original goal of EFM was to assist clinicians in determining both appropriate intervention, by detecting fetuses in early stages of compromise, and appropriate nonintervention, by enabling reassurance of fetal condition to allow for normal vaginal birth and avoid unnecessary maternal risk. Dr. Devoe explained current issues facing obstetrical practitioners and discussed the meta-analysis undertaken by Thacker comparing EFM with the standard of intermittent auscultation, in some instances abetted with fetal scalp blood sampling. The meta-analysis concluded that EFM was positively associated with more operative deliveries, perinatal death rates were comparable to the population receiving intermittent auscultation, and there was a reduction in neonatal seizures when EFM was abetted by an ancillary method. Dr. Devoe discussed ACOG Practice Bulletin #62, which concluded that EFM has a high false positive rate, leads to more operative deliveries, and does not reduce cerebral palsy rates.

Simon Grant, CEO, Neoventa Medical AB, discussed the technical properties and functionality of the device. STAN^®looks at the effect of stress on the fetal electrocardiogram (ECG). The signal is obtained in the same manner as with ECG, but the entire ECG complex is analyzed rather than simply the R wave. First, a baseline must be established, a process which can take 5-20 minutes. The system takes 30 ECG complexes and analyzes the average. Then the device looks at the slope of the ST segment and the amplitude of the T wave compared to the QRS and calculates the T/QRS ratio.

One of the most important things the device looks at is a rise in the T wave amplitude. During hypoxia, there is an adrenalin surge, aerobic metabolism and a resulting increase in T wave amplitude, which results in an increased T/QRS ratio. There are two kinds of ST events in this situation: a baseline rise or an episodic rise where there is a temporary rise in T/QRS.

Another type of ST event is biphasic, a negatively sloping ST segment. When changes are clinically significant, an ST event is generated, and the clinician consults the STAN Clinical Guidelines to decide how to manage the patient.

Mr. Grant explained that STAN includes the standard functionality of an intrapartum and electronic fetal monitor. He explained the difference in the display of the STAN device compared to a standard monitor. The display was adapted for use in the U.S. following recommendations of the Panel, and a training program for U.S. clinicians was also developed.

Mr. Grant described the current use of the device in Europe. Then he discussed the early preclinical research of the technology. These studies demonstrated that an ST rise indicated anaerobic myocardial metabolism and that biphasic ST indicated a reduced ability of the myocardium to respond.

Dr. Devoe reviewed the data originally presented to the Panel in 2002. One study of note was the Nordic Study from 1990 to 1999, which established that the guidelines for the STAN information were able to detect cases of metabolic acidosis. The Swedish RCT enrolled nearly 5,000 patients and showed a 54% reduction of cord metabolic acidosis and a 19% reduction in operative deliveries. Dr. Devoe also talked about the clinical usage trials conducted in Europe. The E.U. Clinical Study demonstrated that the educational materials could be used effectively in different countries and languages. The Gothenburg study also showed a reduction in metabolic acidosis, low Apgar score, seizures, and operative deliveries for fetal distress. Dr. Devoe then discussed the previous Panel meetings regarding the device.

Sue Ellen Abney, RNC, MSN, Perinatal Nurse Specialist, Medical College of Georgia, introduced the U.S. Educational Study. It was designed as a bridge between the Swedish RCT and the U.S. Clinical Use Study. The study focused on mandatory education and training including credentialing and certification of OB physicians and midwives. Total overall accuracy for the U.S. investigators in identifying fetal conditions improved from about 45 to 70 percent with the addition of ST information.

The outcomes of the educational study were used in designing the U.S. Clinical Use Study. Investigators first completed a self-study and a lecture followed by a certification test. Then they used the STAN^®monitor to gather standard EFM data and observe the ST information. They were credentialed based on review of their cases and their understanding of the ST analysis.

Ms. Abney discussed her own observations as the study coordinator at the Medical College of Georgia.

Jennifer L. Ryea, ScM, Biostatistician, Hogan & Hartson, L.L.P., further discussed the U.S. Clinical Use Study. The first primary endpoint of the study, negative predictive value (NPV) of the device, as measured by the percent of cases with non-reassuring fetal heart rate tracings, no indication for intervention based on ST data, and where cord artery pH was greater than 7.12, in which a correct decision not to intervene was made, would ensure that when no intervention was performed there was a high probability of a normal fetal outcome.

The second primary endpoint, agreement of the U.S. clinicians with the STAN experts, measured by positive and negative percent agreements (PPA and NPA), would demonstrate that the U.S. clinicians could implement the device similar to the experts.

Dr. Devoe further discussed the design and results of the U.S. Clinical Use Study. With regard to NPV, analysis across all pH values exceeded 90 percent, well above the success criteria, and the overall agreement, both PPA and NPA, was found to be 90 percent.

A user survey was also conducted. The majority of users found the STAN monitor to be easy to use, and in two-thirds of the cases users felt the device improved their ability to assess the condition of the fetus during labor.

Three conclusions drawn from the studies were that they show a reduction in adverse perinatal outcomes, the STAN educational program has been successfully used in diverse cultures, and that there has been successful technology transfer to the U.S.

Ms. Marlow first emphasized that the device would be used only in term pregnancies as an adjunct to standard EFM. She added that other conditions for use included planned vaginal delivery, need for close fetal surveillance, and in cases of maternal disorders such as utero-placental dysfunction. Contraindications for the device are similar to those for standard EFM.

PANEL QUESTIONS TO SPONSOR

Dr. Noller opened up the floor for clarifying questions from the Panel members. Dr. D’Agostino asked whether the sponsor had done an analysis of the performance of the individual investigators. Ms. Ryea responded that they had had completed that type of analysis and had found nothing of concern.

Dr. Parer asked for clarification whether a non-reassuring fetal heart rate tracing was an indication for the use of STAN, and Ms. Marlow assured him that it was. Dr. Parer then asked whether the T/QRS ratio was a running average. Mihaela Golic, Product Manager, Neoventa Medical, responded that the ratio is not a running average but rather the average of 30 sequential heart rate intervals. Dr. Parer further inquired whether ST events were generated from changes in both T/QRS and ST morphology. Mr. Grant responded that an event would be generated by one or the other, and that the log would record which type of ST event it was.

Dr. Iams raised concerns about the potential use of the device on patients without any of the recognized high-risk indications since it would potentially be used any time an internal monitoring device was used for any reason. Dr. Devoe stated that when there is a reassuring tracing, that tracing should be the main factor in clinical decision-making.

Michael Ross, M.D, M.P.H., Professor of Obstetrics and Gynecology, UCLA School of Medicine and School of Public Health, pointed out that the indication for enrolling patients in the clinical use study was placement of an internal scalp electrode, the same sort of circumstance Dr. Iams was concerned about, and there was no demonstrated increase in operative intervention and no cases of significant metabolic acidosis.

Dr. Iams asked for information on the NPV of all women in the clinical use study who used the device. Dr. Ramin asked whether the device would take 20 minutes from beginning use of the device to provide an ST analysis. Dr. Golic responded that it would depend on the type of event and that the maximum time needed would be 20 minutes.

Dr. Eglinton inquired about how the device would be integrated into central monitoring systems already in place. Mr. Grant responded that they are talking to manufacturers about integrating the technology. Dr. Parer wondered whether there might be another explanation for the improvement of the U.S. clinicians in the Educational Study besides that the ST information helped them. He also wondered about the difference in paper speed between the Swedish and U.S. systems.

FDA PRESENTATION

Kathryn S. Daws-Kopp, lead reviewer, began the FDA’s presentation. She described the history of the FDA review of the device. The sponsor first submitted a PMA in January 2002 after the Swedish RCT was completed. The PMA came before the Panel in April of 2002. In June of 2003 the sponsor again came before the Panel to discuss the Education and Clinical Use studies. The current amended PMA was submitted in February of 2005.

Ms. Daws-Kopp described the components of the STAN^® device. The basis for the mechanism of action is that responses to hypoxia will show up as changes in the ECG waveform. The three types of events of interest are baseline T/QRS rise, episodic T/QRS rise, and biphasic ST.

One issue in particular focused on was the change from the S21 model of the device, used in all of the clinical testing, to the S31, the subject of the amended PMA. FDA was satisfied that the S31 would perform in the same manner as the S21. Bioresearch monitoring and manufacturing reviews have yet to be completed.

Julia Carey- Corrado, M.D., OBGYN Devices Branch, discussed the Swedish RCT, the pivotal clinical trial for the device. For the intent-to-treat population, this study found a statistically significant reduction in metabolic acidosis and in operative delivery for non-reassuring heart rate among patients monitored with both FHR plus ST analysis compared to patient monitored with FHR alone. Regarding safety, the Swedish RCT found no statistically significant difference in Apgars of less than 7 at 5 minutes or in admissions to the NICU.

Dr. Corrado discussed the concerns of the Panel in 2002 and the development and carrying out of the Educational and Clinical Use studies. She concluded by saying that safety and effectiveness were demonstrated by the Swedish RCT. Now the sponsor has promulgated a U.S. version of STAN guidelines, completed two bridging studies, and created an expanded education and training program for the device.

Gene Pennello, Ph.D., Statistical Reviewer, Diagnostics Branch, Division of Biostatistics, talked about statistical design and analysis issues. Diagnostic tests are meant to evaluate the tradeoff between correctly detecting the condition and falsely detecting it. An uninformative test would test positive as often when the condition was present as when it was not.

The STAN tests positive when the clinician intervened before spontaneous vaginal delivery and negative when the clinician does not. Because the studies are interventional and intervention eliminates the possibility of knowing what the outcome would have been without intervention, only the negative predictive value, a measure of non-interventions without the condition, can be calculated without bias. The U.S. Clinical Use Study only looked at negative predictive value. There is some potential bias looking at accuracy in the Educational Study.

Dr. Pennello talked about the difficulty of obtaining a correct p-value for the percent agreement in the Education Study because of correlations in the total pool of readings that were completed. He also discussed the development of endpoints for the Clinical Use Study.

Dr. Pennello summarized the two U.S. studies. In the Education Study, 10 of 13 raters passed the certification test, and there was some variation in the effectiveness of the training. In the Clinical Use Study, of the three endpoints, only PPA was not met.

FDA QUESTIONS AND PANEL DISCUSSION

1. Given the results of the Education Study, does the Panel believe that this shows U.S. clinicians, in a classroom setting, can learn and successfully use the STAN system? Is variation among readers in the effectiveness of training a concern?

Panel members were in general agreement that U.S. clinicians were shown to be capable of using the system, but expressed some concerns about the variation amongst the clinicians in light of the intensity of the training. A panel member wondered whether the results of the Clinical Use Study had been influenced by the fact that some of the clinicians had already received training in the Educational Study. The sponsor clarified that there was no overlap of the participants in the two studies. A panel member pointed out that it is rare for patient monitors to have required training regimens. Dr. Noller agreed that health care facilities generally decide who can and cannot use such devices. One panel member espoused the view that there should be mandatory training for fetal heart rate monitoring and hoped that this new system would have a certification program.

2. The a priori targets for NPV and NPA were met, but the lower bound on the 95% CI for PPA was 68% (versus the 75% target). Considering the various analysis strategies, please discuss the clinical implications of these findings. Does the CUS Study demonstrate that U.S. clinicians can learn and successfully use the STAN technology in the clinical setting?

A panel member stated that he did believe the CUS study showed that U.S. clinicians can learn the STAN system. The sponsor, responding to an earlier question, stated that the NPV did not change much when women with normal tracings were included. A panel member inquired whether any women had interventions in spite of a normal tracing because of an ST event. The sponsor responded that five of 291 women fit that category and clarified that they were indeed intervened upon unnecessarily, as verified by the cord gases. Members asked whether the fetal EKG functions could be turned off and the device used as a standard monitor, and the sponsor stated that it could be used in such a way. The discussion turned to the question of the target population for the device and whether it should be indicated only for cases with non-reassuring fetal heart rate or for all laboring patients. A panel member raised the issue that the device needs a 20 minute baseline so waiting for non-reassuring fetal heart rate to develop before turning on the device wouldn’t necessarily work. Another panel member was concerned about who would be monitored with the device and thought it was unrealistic to expect that only high-risk patients would be. A panel member pointed out that 80-100 percent of mothers have continuous EFM so the question of which patients will be monitored is practically moot. With certain exceptions, e.g. cord prolapse, there is an evolution from normal to abnormal fetal heart rate tracings. At some point during this evolution from normal to abnormal, the clinician begins to get concerned. This is when it would become useful to activate the ST analysis.

3. Do the results from these two bridging studies conducted in the U.S. (Education and CUS), when considered along with the previously reviewed studies (e.g., the Swedish RCT), collectively demonstrate the safety and effectiveness of the STAN S31 Fetal Heart Monitoring System for its stated indication for use?

A panel member stated that the studies taken together did demonstrate safety and effectiveness, but stressed the need for an intensive and ongoing educational program. He also suggested that perhaps a few people in each health care facility should take the lead on maintaining standards for use of the device. Other panel members agreed that the device was demonstrated to be safe and effective.

4. Does the panel have any comments on the labeling and instructions for use provided by the sponsor?

Panel members discussed the idea of “need” with regard to the indications and acknowledged that most women monitored in this country do not need to be. A panel member mentioned that the device might be able to be used to increase the possibility of a safe vaginal delivery. One panel member added that the device was also effective at reducing acidemia. The sponsor talked about identifying centers of excellence that can help train clinicians from other centers, and super users that could take the lead within individual health care systems. A panel member raised the issue of using the device in other than term pregnancies, for which there are no data.

5. Does the panel believe that the STAN Educational Program used for the U.S. Clinical Use Study together with the existing Continuing Education opportunity available on the Internet should be basic requirements of STAN training for U.S. clinicians if the PMA is approved?

Panel members discussed the need for Department Chairs to require training. Ms. George talked about sponsor monitoring of adverse events associated with devices. The sponsor discussed the time needed for training and the spread of the information among clinicians. A panel member inquired about the use of the device for twins and to aid with arrhythmias. The sponsor replied that the device could not be used with normal twins and is useful with only certain specific arrhythmias. One panel member raised a concern about the difficulty of interpreting the ST data in the setting of a woman in labor. There was discussion about whether FDA should require users of the device to be trained. A panel member suggested there should be mandatory training because of the potentially far-reaching impact of the device and so that hospitals cannot skip the training to save money. Panel members agreed that there should be mandatory training.

6. Does the panel have any input regarding any issues that should be addressed in a post-approval study?

Panel members generally agreed that there should be tracking of the rates of cesarean section and acidemia at the first centers to adopt the device. One panel member suggested that a post-approval study should look at whether clinicians are being properly trained. Another panel member suggested that rates of use and indications for use should be examined.

OPEN PUBLIC SESSION

Thomas Frank, Perinatronics Medical Systems, began by stating that the panel seemed to have no doubts that the device under consideration was intrinsically safe and clinically effective. He discussed the need to clarify terminology. He stated that the device provided an opportunity to monitor a new physiologic parameter for the benefit of patients.

FINAL FDA COMMENTS

The FDA had no final comments.

FINAL SPONSOR COMMENTS

Ms. Marlow thanked the panel members for their hard work and a fair review of the PMA.

VOTE

Panel Executive Secretary Bailey read the voting options. Dr. Noller asked whether there was a motion to recommend approval, approval with conditions, or not approvable. Dr. Ramin put forth a motion to approve the device with conditions; Dr. Wing seconded the motion. Dr. Noller asked for motions for the individual conditions

Dr. Ramin put forth a motion that the sponsor should outline a program to educate the clinicians who will use the device. Dr. Iams seconded the motion. Dr. Hillard asked whether the motion was intended to include certification, and Dr. Ramin said that it was. Drs. Parer and Cedars stated they would like to see surveillance of the efficacy of the training provided. The panel members discussed the sponsor’s role in the training. Dr. Noller clarified the motion to be that the sponsor be required to develop educational materials leading to certification in the use of the device and to present implementation plans for education and certification to each new clinical setting. Drs. Ramin and Iams agreed with his restatement of the motion. The motion was approved unanimously.

Dr. Parer moved that there be a requirement for a post-approval study of the primary study endpoints, C-section and acidemia rates following introduction of the device. Dr. Iams offered a friendly amendment to also include the endpoint of operative delivery. Dr. Parer accepted, and Dr. Iams seconded the motion. Dr. Parer clarified that the study would need to be done appropriately but left those details open. Dr. Hillard offered as an amendment that there be an assessment of the rates of use and indications for use. Drs. Parer and Iams agreed. Ms. George stated that much of the data would already be collected by the hospitals, and Dr. Noller agreed that some of the data could be obtained from the hospitals. Dr. Noller stated that data on indications for operative deliveries would be difficult to obtain. Dr. D’Agostino cautioned that the burden for obtaining the data from the hospitals should be on the sponsor. Dr. Noller said that the details of the study would be worked out by the FDA and the sponsor. Nancy Brogdon, Director, Division of Reproductive, Abdominal, and Radiological Devices, agreed and said the FDA was most interested in knowing what data the Panel thought should be studied.

Dr. Eglinton wondered about the difficulty of getting information on usage rates. Dr. Noller suggested there be some allowance for whether getting those data would be feasible. Dr. Iams suggested that the study should look at less information, and Dr. Parer agreed. Dr. Parer wondered what would happen if C-section and acidemia rates went up after introduction. Ms. Brogdon stated that the PMA approval could be withdrawn or the labeling be restricted. Dr. Doyle suggested that the panel was essentially requiring the sponsor to obtain information on off-label uses. Dr. Iams suggested that the potentially widespread use of the device without informed consent justified consideration of off-label usage. Dr. Eglinton discussed how C-section rates have gone up during his career and wondered whether further increases could justifiably be attributed to the device. Dr. Noller agreed. He restated the motion as requiring the sponsor to conduct a survey on the primary endpoints from the studies already conducted, rates of operative deliveries, acidemia, and neonatal encephalopathy; certification of clinicians; and indications for use and rates of use, if possible. The motion passed with eight voting for, one against, and no abstentions.

Dr. Cedars moved for a condition that there be a change in the labeling to say the device is an adjunct for the assessment of non-reassuring fetal heart pattern. Dr. Parer seconded the motion but asked that the terminology be left open. Dr. Cedars stated that the panel needed to use the standard terminology. There was no other discussion. The motion passed unanimously.

Dr. Eglinton put forth a motion that each device be delivered with an education package including a textbook, a CD-ROM certification test, credentialing materials, a test, and continuing education materials. Dr. Iams seconded the motion. There was no discussion. The motion passed unanimously.

Dr. Miller moved that the labeling for the device exclude twin gestations. Dr. Iams seconded the motion. There was some disagreement on what the sponsor had said about twins. Ms. George pointed out that the user documentation stated that it was not possible to monitor both twins with the fetal ECG. Dr. Miller withdrew his motion.

Hearing no more conditions, Dr. Noller called for a vote on the motion to approve Neoventa’s PMA P020001 for the STAN S31 Fetal Heart Monitoring System with the four conditions just approved. The motion passed unanimously.

Dr. Noller asked each panel member to state the reason for his or her vote.

Dr. Doyle said that the device had the potential to identify fetuses in trouble and those who were not in trouble, thus the device posed minimal risk to the patient.

Ms. George thought the voting members had made a great decision and reiterated that data for the post-approval study would already be collected by parties other than the sponsor.

Dr. Wing stated that the data were convincing, that there were no safety concerns, and that this device added a potential benefit of reducing acidemia and operative deliveries.

Dr. D’Agostino said that the Swedish study demonstrated safety and effectiveness, and that the bridging studies had addressed the Panel’s concerns about the use of the device in the U.S.

Dr. Iams agreed with the previous comments. He urged the FDA and the sponsor to take seriously the task of promoting the device as being intended to identify patients who do not require an intervention.

Dr. Miller agreed with the previous comments and was glad to have another tool to assess the fetus.

Dr. Cedars agreed with the comments about the Swedish study and the bridging studies.

Dr. Ramin stated that the device had been demonstrated to be safe and efficacious, and that concerns about its use in the U.S. had been addressed.

Dr. Hillard also agreed with the previous comments and expressed excitement about the possibility of improving the use of existing technologies and decreasing cesarean rates.

Dr. Parer believes that the device is safe and effective, and that the conditions imposed would provide information about its safety and effectiveness in the broader medical community.

Dr. Eglinton believed that the sponsor had satisfactorily demonstrated safety and effectiveness in accordance with the law.

ADJOURNMENT

Dr. Noller thanked the Panel members for their preparation and adjourned the meeting at 3:49 p.m.

I certify that I attended this meeting of the Obstetrics and Gynecology Devices Advisory Panel Meeting on May 17, 2005, and that these minutes accurately reflect what transpired.

______________________________

Michael Bailey, Ph.D.

Executive Secretary

I approve the minutes of this meeting

as recorded in this summary.

_________________________________

Kenneth L. Noller, M.D.

Chairperson

Summary prepared by

Eric C. Mollen

Neal R. Gross & Company

1323 Rhode Island Ave., N.W.

Washington, D.C. 20005

(202) 234-4433

SUMMARY MINUTES

SEVENTIETH MEETING OF THE OBSTETRICS AND GYNECOLOGY DEVICES

ADVISORY PANEL

Consumer Representative

Industry Representative

OPEN PUBLIC HEARING

VOTE