Open Public Hearing
DR. STEINBERG: Thank you, Mr. Chairman. As you said, I am Vice President of Covans Health Economics and Outcome Services which is a contract research organization. I also am an adjunct professor of medicine, radiology and health policy and management at Johns Hopkins University where I was the Director of Technology Assessment for eight years.
I would like to congratulate the investigators on what I believe is a creative study design for a very challenging methodology problem, namely demonstrating the noninferiority of the comparability of digital and screen-film mammography. I also am pleased with the FDA's positive reaction to the studies that were presented.
The issue that I would like to address is what conclusions can be drawn from these studies regarding the performance of digital mammography or, for that matter, screening mammography, in a diagnostic versus a screening population and what the implications of those conclusions might be for the issue of whether this is judged to be substantially equivalent or whether it is judged to be effective in a PMA sense.
Dr. Sacks and other FDA officials have indicated today their concern that diagnostic performance may be different in a screening than in a diagnostic population. For example, digital mammography might perform comparably in a diagnostic population but less well than screen film in a screening population.
This, in fact, was one of several reasons that Dr. Sacks offered for wanting to have a postmarketing study. If, as the FDA has suggested, digital and film-screen mammography may perform differently in these two populations, then there is not enough statistical power in these studies that were presented today to assess the performance of digital mammography in either diagnostic or in a screening population.
The reason for that is that the analysis is based, as was indicated by Dr. Byrd, on a mixed or a hybrid population and, hence, the only conclusion that can be drawn from the data that was presented today is that safety and digital mammography are, in essence, substantially equivalent in mammography.
We do not have enough data to conclude with any confidence that digital mammography is non-inferior in diagnosis or non-inferior in screening as, I believe, would be required for a PMA.
I would like to ask what we know from the application about the width of the 95 percent confidence intervals around the deltas for sensitivity, specificity and the areas under the curve when the two populations are separated and looked at individually.
My suspicion is that they at least double and, hence, they would not satisfy the criterion in either case. I, therefore, would urge you to approve this technology but as being substantially equivalent to screen film without making any reference to separate performance in diagnosis and screening separately.
DR. GARRA: Thank you. You didn't mention financial interests. Could you please mention that for the group?
DR. STEINBERG: I apologize. I have been a consultant for over two years to Fuji.
DR. GARRA: Thank you.
DR. KOPANS: Dr. Daniel Kopans, again, Director of the Breast Imaging Division at the Massachusetts General Hospital, Professor of Radiology at Harvard Medical School. I should also point out, as you heard today, we provided a number of the General Electric images and received some support for that.
To those of us, I think, sitting in the audience, it was pretty clear that General Electric has clearly established equivalency between digital mammography and film-screen mammography. I think to those of us who have used the technology, digital mammography, that was obvious.
I am concerned that the FDA has locked itself into a PMA process and I am concerned about the requirement for postmarket approval studies. I think Dr. Harms has pointed out some of the important issues which I would just, again, summarize. I think that the rationale, at least one of the rationales, that FDA gave this morning for wanting a PMA approval was based on the cervical Pap smear automated interpretation system.
As Dr. Harms has pointed out, that has absolutely nothing to do with the digital acquisition of a mammogram. if you were talking about computerated detection and diagnosis, then you would have comparability. So the fact that FDA is using that as a rationale, to me seems illogical.
I think it is also of concern, especially to us who have used the technology and have seen how well it performs, that a study that would require double exposure of individual again, as was pointed out by the panel, would raise some major ethical concerns.
Dr. Sacks pointed out, and he actually cited some of our work, that getting extra mammograms increases the yields of cancers. This is nothing new, actually. There were studies back in the 1980s that show that the more projections you obtain, the more cancers you find.
If you wanted to back a study to show that again, maybe we should be getting three projections on every individual. That I think is ethically supportable. But to use that as a rationale for double-exposing women to prove what is already shown to be equivalent I think is a major problem and I think doing any of these large studies would raise ethical concerns.
So, in summary, I would again, as I said at the beginning but, again, having heard now General Electric's presentation, I would urge the panel--I know FDA doesn't have to do what the panel suggests, but I would urge the panel to strongly support approval with a 510(k) mechanism. I think that, again, equivalency has been clearly shown and I would like to see us now move ahead to improving this technology as well as others and not waste scant resources on just showing that mammography is equivalent to mammography.
DR. GARRA: Thank you.
What we are going to do at this point--we don't have any more people who have asked to speak. We are going to take a fifteen-minute break at this point and then we will reconvene at ten minutes of 3:00 and then we will have final votes and everything.
Thank you very much.
DR. GARRA: I would like to begin the final session of this panel meeting. Before we move to the panel recommendations and vote, is there any additional material the FDA would like to address?
DR. CHAKRABARTI: I am Kish Chakrabarti. I am with the Division of Mammographic Quality and Radiation Performance, DCRH, FDA. I have one point to clear, that, under MQSA, FDA required that for any modality, any mammographic modality, maximum allowed dose per image is 300Êmillirad. That is under the final regulation.
DR. GARRA: Any other comments by the FDA?
Now the sponsor, General Electric, has a chance to make any final comments they would like to make.
MR. DONNELLY: Thank you, Dr. Garra.
I don't have any more substantive comments. I want to take the panel. We appreciate the time today and your thoughtful consideration. Based on the questions, obviously there was a great deal of review time that went into preparing for today's session on your part.
I also thank you for the insight relative to the postapproval studies. It is clear this has been a much-discussed item between ourselves and the FDA in terms of a meaningful study. I think we all are more or less in agreement relative to the issue of soft copy and I think those comments will help us considerably in terms of trying to go forward to determine an appropriate postmarket approval study.
I also want to thank the FDA. It has been a long several years in working on trying to seek approval for this technology to get it into the marketplace. The interest on G.E.'s behalf has been to try to do this and do this as quickly as possible based on what we think is the strength of the clinical studies.
While there have been a number of changes and what not along the way, I would have to say that in the last few months after the meetings and concurrence to pursue a PMA path that there has been a lot of cooperation on the part of the FDA and I think we have worked very closely and appreciably with them to make sure that we can get the new technology to the market as soon as possible.
So thank you very much.
DR. GARRA: Thank you.
Panel Recommendations and Vote
DR. GARRA: We are now ready to move to the panel's recommendation concerning PMA P990066. The Medical Device Amendments to the Federal Food, Drug and Cosmetic Act as amended by the Safe Medical Devices Act of 1990 allows the Food and Drug Administration to obtain a recommendation from an expert advisory panel on designated medical-device premarket approval applications, PMAs, that are filed with the agency.
The PMA must stand on its own merits and your recommendation must be supported by safety and effectiveness data in the application or applicable publicly available public information.
There are several things we consider. Safety is defined in the Act as reasonable assurance based on valid scientific evidence that the probable benefits to health under conditions of intended use outweigh any probable risks.
The effectiveness is defined as reasonable assurance that, in a significant proportion of the population, the use of the device for its intended uses and conditions of use, when labeled, would provide clinically significant results.
We have several possible options for our vote. The first is approve with no conditions. The second is approvable with conditions. The panel may recommend that the PMA be found approvable subject to specified conditions such as physician or patient education, labeling changes or further analysis of existing data. Prior to voting, all of the conditions should be discussed by the panel.
The third choice is not-approvable. The panel may recommend that the PMA is not-approvable if the data do not provide a reasonable assurance that the device is safe or, if a reasonable assurance has not been given, that the device is effective under the conditions of us prescribed, recommended or suggested in the proposed labeling.
At this point, the Chair will entertain any motions regarding approval or disapproval of this PMA.
DR. DESTOUET: Mr. Chairman, I recommend approval of PMA P990066 without conditions. I recommend that the manufacturer deploy the soft-copy work station to serve as an adjunct and/or to replace the hard-copy images for evaluation of mammography.
DR. SMATHERS: I would like to second that.
DR. GARRA: Thank you. Dr. Smathers has seconded that. Did somebody write that down? Bob, could you read that back to us again, please?
MR. DOYLE: Yes. The motion is to approve the PMA without conditions with a recommendation that the manufacturer deploy soft-copy work stations to serve as an adjunct to hard copy.
DR. GARRA: This motion has been moved and seconded. Is there any discussion on this? We should probably go around the table and everybody sort of has to give discussion.
DR. HARMS: I agree. I feel that further studies would not be warranted at this time and would be a not-essential use of resources of both the FDA and industry.
DR. MALCOLM: I agree with the comments. Clearly, I think it has been demonstrated that at least this technology, as we know it today, is equal, at least on hard copy as we see, for the studies as compared to film mammography. I think there is also additional data that is out there that, perhaps, was not presented that shows that we are actually beyond that point and I am not sure if we need this additional postmarket studies which, I think, perhaps is not cost effective.
DR. GARRA: I, myself, agree with the motion. I would ask the panel to please consider if we do need to make any minor suggestions regarding the labeling section of that. Sometimes, that gets lost in the shuffle, but I also don't feel that, given the other data that is out there that is publicly available, so if we could use it in our determination, that a postmarket study is absolutely necessary.
I would suggest, however, that if one is done that it definitely include the soft-copy component.
DR. BERG: I would agree with your comments, Brian. I think that there is data already from the Army-sponsored study that would answer the issues that were raised by the FDA for postmarket surveillance. I think that data needs to be made available to the FDA. It is already part of public record, ultimately.
DR. ROMILLY-HARPER: I agree with most of the comments that have already been made.
DR. SMATHERS: I concur.
DR. TOLEDANO: Ditto.
DR. GARRA: Any other further points specifically regarding the labeling issues or anything that anybody would like to bring up? Dr. Smathers?
DR. SMATHERS: Your comment about an executive summary in the front of that, I think, is very germane. This is so long that no one is going to read it. I think a clear synopsis has to be put together.
DR. GARRA: Would you like to amend the motion to include that?
DR. SMATHERS: Yes.
DR. GARRA: Do we have a second to that?
DR. GARRA: We are amending the conditions section to say that we would like a change to the labeling.
MR. DOYLE: You are approving it with conditions.
DR. GARRA: Yes.
MR. DOYLE: To include an executive section in the front of labeling.
DR. GARRA: Or something equivalent to that that emphasizes the difference between this study and a true screening or diagnostic study.
DR. SCHULTZ: We are talking about the clinical section of the labeling? Is that what we are discussing?
DR. SMATHERS: Yes.
DR. SCHULTZ: Not the summary of safety and effectiveness. You are talking about the labeling, the way the clinical data is presented in the labeling, that you would like it done more succinctly emphasizing the differences between--or the way that the studies were done? Is that it? Or study populations?
DR. GARRA: I think instead of deleting all the stuff that is in there, what the idea was was to add one paragraph that summarized it in a few sentences figuring that that is--
DR. SCHULTZ: Summarizes where the study populations were drawn from? Is that the major--
DR. GARRA: How they differ from a true screening and a--
DR. SCHULTZ: And a true diagnostic population. Okay.
Could I ask for one more clarification with regard to the hard-copy/soft-copy issue? I am assuming, and maybe this is not a good thing to assume, but I am assuming that you don't want to wait for the soft copy to be available to have this device approved. Is that true? Because the way the recommendation is worded, it is a little confusing as far as I can tell.
Right now, the submission that is before you is for hard copy. I think the proposal that has been made, both by the company and by the agency, is that we would work together to try to achieve a soft-copy approval within a very, very short period of time following the original approval.
But, currently, we do not have a submission before us for soft copy so we--
DR. GARRA: We are not recommending an approval of a soft copy. We are recommending that it be deployed for evaluation.
DR. SCHULTZ: That the studies be done to get it approved as quickly as possible; is that what you are saying?
DR. GARRA: Yes, essentially.
DR. HARMS: My opinion is that you would expedite that integration of soft copy and the final product. We realize we do not have soft copy to review at this time.
DR. SCHULTZ: Okay.
DR. GARRA: We just wanted to emphasize the importance of going to soft copy in that recommendation.
DR. SCHULTZ: We hear you loud and clear.
MR. DOYLE: The way I see this now, we have approvable with conditions. There are three conditions and we have to vote on each one of these conditions separately. This is how we conduct our business.
So first we want to take a vote on approvable with conditions as a general motion.
DR. SMATHERS: What are your three conditions?
DR. GARRA: Judy?
DR. DESTOUET: Do I have to resubmit the motion?
MR. DOYLE: You have to withdraw the motion.
DR. GARRA: We have to withdraw that motion in favor of the one with the amendment.
DR. DESTOUET: I withdraw my original motion.
MR. DOYLE: And put a motion forward to approve it with conditions and we will see if that gets seconded.
DR. DESTOUET: I recommend that we approve the PMA with conditions.
DR. SMATHERS: I will second that.
MR. DOYLE: All in favor?
[Show of hands.]
DR. GARRA: We shouldn't have to do that until we hear what the conditions are.
MR. DOYLE: No; this is the process.
DR. HARMS: Why can't we approve without conditions? We were not privy to this discussion here.
DR. GARRA: The condition was the modification of the labeling to include a short summary.
MR. DOYLE: And the expediting of the soft copy and the recommending that the manufacturer deploy soft copy. I have written down three conditions.
DR. GARRA: That's fine. All those in favor of approval with conditions, please raise your hands.
[Show of hands.]
MR. DOYLE: It is unanimous. Now, we are going to take each one of these conditions. I will read them. The first condition is recommending that the manufacturer deploy soft-copy work stations to serve as an adjunct to hard copy.
DR. GARRA: All those in favor of that suggestion raise your hands?
[Show of hands.]
MR. DOYLE: It is unanimous.
DR. GARRA: Please read the second one.
MR. DOYLE: The second one is, have an executive section in front of the labeling that emphasizes the differences between the study population and a true screening and/or diagnostic population.
DR. GARRA: All those in favor raise your hands?
[Show of hands.]
MR. DOYLE: It is unanimous.
DR. GARRA: And the final one?
MR. DOYLE: The final one is expedite the approval of the soft-copy modality.
DR. GARRA: All those in favor.
[Show of hands.]
MR. DOYLE: Now we have three. Now we just go back and approve the motion with those three conditions. So one more vote.
DR. GARRA: We will certainly have this documented.
MR. DOYLE: Does someone want to second that motion?
MR. DOYLE: All in favor of approving with those three conditions that have been approved.
[Show of hands.]
MR. DOYLE: Unanimous again. Now we would like to go around and just--
DR. GARRA: Let's just quickly go around. We have already discussed this a little bit. Let's quickly go around and recap the reasons why each of you voted the way that you did.
DR. HARMS: I believe the device and the data that is submitted is safe and effective and that it represents a significant advance for the diagnosis of breast cancer and should be integrated into clinical practice as well as possible.
DR. MALCOLM: Agree.
DR. GARRA: I voted this way because I feel that these recommendations will best expedite the integration of digital mammography into clinical practice and puts the emphasis on moving towards soft copy in an expedited fashion.
DR. DESTOUET: The manufacturer has shown that the equipment is safe and effective.
DR. BERG: I agree and I would add that I think that there has been the demonstration of substantial equivalence although I know that is a controversial issue.
DR. ROMILLY-HARPER: I agree that the manufacturers have proven that the device is safe and effective and this technology will certainly improve the diagnosis of breast cancer and availability, hopefully, eventually to women.
DR. SMATHERS: I concur with the earlier comments and, in my parting piece of wisdom to the FDA, would suggest that, as you look at different detectors that come in, there will be slight differences. I would ask that you grant them a bit of latitude, that the net effect of the differences in the detectors isn't going to be that great and that, perhaps, they won't have to jump as many hurdles as General Electric had to.
DR. TOLEDANO: I agree with my esteemed colleagues on the panel.
DR. GARRA: Mr. Doyle, would you like to make a final comment?
MR. DOYLE: Yes; all I would like to do is thank the panel, certainly, for coming here to this unscheduled meeting and I appreciate every one of you getting--100 percent attendance was really fantastic. All I need back from you, and if you don't have it here today, you can send it to me, is the orange book. All the rest of the materials that you were given today, you are welcome to take home.
DR. GARRA: Before we adjourn, I would like to thank the speakers, the members of the panel for their preparation for this meeting which I think, as meetings go, is sort of historic. I would also like to extend thanks to the people from the audience, the public, who commented. I think your comments are very helpful and will be given careful consideration.
I would like to extend special thanks to Judy Destouet for leading the discussion segment of today's meeting.
If there is no further business, I would like to adjourn this meeting. Thank you.
[Whereupon, at 3:20 p.m., the meeting was adjourned.]
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