Some very interesting exchanges can be found in FDA transcripts, exchanges which foreshadowed problems that the victims of refractive surgery knew about, but couldn't get anyone to pay attention to, because no one was interested. These transcripts are a matter of online public record, meaning that they are to be permanently warehoused on the FDA servers. Yet, some of these transcripts have mysteriously disappeared. When you write to the webmaster for the FDA, at first they're eager to help you. But eventually, you just get no reply and no documents.
The FDA Alcon Approval Meeting
Background: Meeting was held Aug. 1, 2002 in Gaithersburg, Maryland. The purpose of the meeting was to review the clinical trial results and vote on ALCON's application for FDA approval of CustomCornea wavefront guided LASIK for the correction of myopia up to -7D. The Surgical Eyes Foundation was represented by Ron Link (founder) and David Shell (a patient) during the open public hearing. A letter from an SE participant was read aloud during the open public forum asking that large pupils and dry eyes be listed as contraindications. Below are notable quotes from that meeting, indexed by their page number on the original FDA meeting transcripts. The quote tell a revealing story of an FDA which have more interest in supporting an unethical industry than in protecting patients.
Page 61 - DR. PETTIT (Alcon): The little asterisks indicate those changes that were statistically significant between the preop and the six-month postop interval and you can see that for almost all of the aberration parameters, they're actually slightly higher by a statistically significant amount after surgery than before. The trefoil is actually less after treatment but it's not a statistically significant difference. Now, I should just also mention this is based on a 6.5mm wavefront analysis diameter. This isn't a surprising finding. It's well known that LASIK tends to increase the higher-order aberrations.
Page 65: Dr. Brint (Investigator): As clinicians, we know that prior studies of conventional LASIK in general have shown that higher-order aberrations, particularly spherical aberration which is frequently linked to poor night vision, occasionally may be increased after conventional LASIK. These increased higher-order aberrations after conventional LASIK are pupil-size dependent with larger pupils showing decreased retinal image quality as measured by point spread function and modulation transfer function and visual performance as measured by the clinically useful contrast sensitivity testing and low-contrast visual acuity testing. (This paragraph is significant to those with large pupils who were not warned, and because there are still doctors saying that pupil size is not a critical measurement prior to surgery.)
Page 66: We know that greater higher-order aberrations are seen in these larger dark-adapted pupils as opposed to the smaller light pupils.
Page 83: Dr. Matoba (FDA panel): In looking at your protocol, I didn't see any reference to pupil sizes as either exclusion criteria or inclusion criteria. Is that taken into account when you were entering these patients?
DR. PETTIT: (Alcon) I have to defer.
DR. MATOBA: And the reason I ask is because the 50 patients who had the conventional ablation were done earlier in the study than the Custom ablation patients in general, correct? And I wondered if there might be a difference in the average pupil size between the two groups and that may affect patient satisfaction or other visual tests.
DR. PETTIT: Okay. The entry criteria did not change over the course of the study.
DR. MATOBA: If you didn't take pupil size into account, then how would you know what they may have been in those patients that were entered?
DR. PETTIT: We can look at pupil size. Do you want to speak? Okay. Let me make sure I have the question down exactly right. For this conventional comparative group, did we control for pupil size or did we have an analysis baseline?
DR. MATOBA: I'm sorry. Go ahead.
DR. PETTIT: Well, I want to make sure I get it right. Did we analyze the data based on pupil size to see if there was any statistically significant difference in pupil size between those eyes and the wavefront group?
DR. MATOBA: Well, my main question is could there have been a significant difference in the average pupil size between the patients who had Custom ablation versus people who had conventional ablation?
DR. PETTIT: Okay. So you're concerned that there might be a significant difference in pupil size between the two groups?
DR. DURRIE (Investigator): I can just comment from an investigator standpoint, is the inclusion criteria were the same throughout the study, and the conventional eyes were done fairly contemporary because initially we did a group with the same algorithm. We did a group that had one eye with conventional and the one eye with Custom. The reason that the number is small is when we drop it down just to spherical cohort, then it gets us down to only 50 eyes. So these were done at relatively the same time period. It's not like one group was done three years ago and one group was done a year ago, and the inclusion criteria regarding pupil size was the same. I think it is interesting, and I think it'd be a good thing to look at, is to actually analyze, since the aberrometer itself records pupil size, so that data is available, and it would be a good thing to continue to look at. I think with all these things, we're coming up with new things we can look at because now we have a digital instrument that can actually give us data that we haven't had before.
Page 89: DR. OWSLEY (FDA consultant): Thank you. I just wanted to make sure I'm understanding your low contrast acuity data properly. It appears that whether we look at the sphere analysis or the all eyes analysis, 20 percent or one in five patients experienced a loss in low contrast acuity. I know that's different, lower than the rate in the conventional surgery, but I just want to make sure I understand. Twenty percent of the patients, one in five, experienced at least a one line or greater loss?DR. PETTIT: That is correct.
DR. OWSLEY: Thank you.
DR. WEISS (FDA panel chairman): Dr. Huang, please.
DR. HUANG (FDA consultant): I just want to ask. Since we set out to try to correct the higher-order aberrations by this application, but the end result shows that there were general increase of the higher-order aberrations, and I don't know if the clinicians or the sponsor have any kind of comment regarding the outcome.
DR. PETTIT: It is true that even after our wavefront-guided surgery, that the higher-order aberrations are generally higher. They're higher by an amount that's significantly much less than what we get with our conventional surgery. We believe that's beneficial to the patient. Our theoretical endpoint is to make them zero, and we clearly are not achieving that yet, but by shooting for that as the theoretical target, we are limiting what happens to them and that's where we are with the current state of the technology.
DR. HUANG: But my point is, instead of reducing, now we are actually increasing. So what's the future direction in that regard?
DR. DURRIE: Dan Durrie. From a clinical standpoint, this is a step along the way because before we weren't even measuring the patient's preoperative aberrations, other than sphere and cylinder. Now we're finding other things that we find clinically significant in the population now that the aberrometer can measure. (Comment: How long have they being doing refractive surgery?) As George said in his presentation about the progress, we found out then that there was some surgically-induced aberrations and some of them were predictable. I think as time goes on, we will learn more about the surgically-induced aberrations and then may have to make compensations. I think it's going to be important for all of us to start thinking about how are we going to accomplish that from a regulatory standpoint when you come up with the next new iteration, so it isn't so onerous that the companies cannot pursue that, and it isn't too onerous from a regulatory standpoint, and I think it's something that I know that you're having a meeting tomorrow to talk about phakic eye welds, but I'd certainly like to have us continue to have a discussion between the sponsors and the clinicians and the agency about once we get better, what do we do then? Because I think this is a step along the way, but we still would like to make that zero, and we're going to have to continue to evaluate data in order to make that happen.
Page 94: DR. GRIMMETT: (FDA panel) I just had an observation and would like to hear if you have a comment. You may have none. There may be no answer. I found it curious that despite a very comprehensive analysis and sophisticated technology, that the patients that were unsatisfied or extremely unsatisfied approximated 9 percent. It's notable that the PERK study (years ago) by comparison, using bear skins and stone knives, had an 11-percent dissatisfaction rate, and I found it curious that one in 10 patients are unsatisfied, despite a phenomenal amount of technology and analysis, and I would like to commend you on a superb analysis and presentation.
Do you have a comment why it's still one in 10 despite all the sophisticated technology or is there no answer to that, sir?
DR. PETTIT: No. Well, I don't know everything. I didn't personally speak to these patients. [snip] I think, you know, in all honesty, in addition, there's a lot of hype surrounding this procedure, and I think their expectation levels in some cases was pretty high, but, you know, that's not scientific. That's just an opinion.
DR. PETTIT: Just to follow up a little bit on an earlier question. This is George Pettit from Alcon. I think Dr. Matoba asked the question about the pupil sizes and were the patients informed. Given this high-level expectation, it's important to note that the optical zone was 6.5mm and we informed all patients considering being in the trial that if their natural pupil was larger than 6.5mm, even with this new technology, there was a potential risk for them to have night vision symptoms. So we tried to bring their expectations more in line.
DR. BRADLEY: (FDA panel): I'm just curious about the apparent huge discrepancy between what Ron Link presented earlier today and the data on the symptoms presented by the sponsor. For example, Ron Link indicated that dryness and double vision are huge problems, and I think we have a couple of other people indicating that, and I look at the data you just presented on dryness where we have slightly more patients indicating worse dryness than those indicating better, and we have a very small number indicating increased double vision, about the same as those who are indicating decreased double vision.
So from the sponsor's dataset, it appears that we don't have this very large and disturbing incidence of dry eye and optical problems, such as double vision, whereas Ron Link and a couple of the other presenters indicated that these are very serious problems, and I wondered therefore if we could clarify perhaps some inclusion criteria from the sponsor because one wonders if Mr. Link's dataset is rather biased to those who have the problems and somehow you have been able to effectively filter these people out of your datasets. Yours are biased the other way. I think it's very important to get a sense of that, particularly for those people who are going to utilize this technology, and if you have effectively avoided these problems by your patient selection criteria, then this clearly should be included in the final labeling for this device.
DR. WEISS: I would just add one thing. On Table 34, if we include the patients in the spherical cohort who are saying that their symptoms are not only significantly worse but just plain worse, you actually have about 32 percent saying the dryness was worse or significantly worse. So it's still not trivial, and I think if we are looking at the worse category, it significantly increases the number of complaints.
Page 108(The following response was obtained when asked why the sponsor was not seeking approval for the correction of astigmatism). DR. PETTIT: No, I'm happy to answer the question. The honest answer is that in the astigmatic cohort, we did meet all the safety parameters as Dr. Durrie indicated, and we were effective, but in an honest assessment, we were not as effective as our conventional surgery in the treatment of astigmatism.
DR. PETTIT: Just real quick. We were able to pull one answer to one question that was asked earlier. For the spherical eyes in the Custom cohort, the mean pupil mesopic pupil diameter was 5.63mm with a standard deviation of .89, and for the comparative 50-eye conventional cohort, it was 5.78 plus or minus .081.
Dr. Bradley: Very important thing to point, though, Number 3, wavefront-guided LASIK procedure increased the level of higher-order aberrations relative to the preop levels. This is an extremely important point to keep in mind.
Page 182Dr. Weiss: Table 10 has the loss of best-corrected visual acuity, and there were 8.6 percent who lost one line, which is significant in my book.
Dr. Swanson: (FDA consultant): Basically half of the people ended up with uncorrected visual acuity after the operation that was worse than the best spectacle-corrected had been,
On page 11, there's a list of subjective symptoms and the list is the significantly worse, and I think, I would personally like to expand the table to the full Table 35, at least showing the worse and significantly worse because the significantly worse may only be a couple of percent where if you include the worse symptoms, you may have 23 percent, and I think this is sort of alluding to what Mr. Link and the other people were referring to in the public session, is that they don't really have a full idea of what they're getting into.
So I personally would prefer if the subjective symptoms had not only the significantly worse but those patients who also had worse symptoms.
I also would bring this out to the panel. Should we include for the patient, maybe also for the docs as well, Table 10 talked about not just two lines of best-corrected visual acuity loss but one line of best-corrected visual acuity loss, and we could also have for Dr. Bradley the gain in visual acuity to be fair because it was 8.6 percent of patients who lost one line of best-corrected visual acuity. As a patient, I think I would want to know that.
I would suggest to include Table 10, and Table 13 had change in low contrast best-corrected visual acuity, and you lose low contrast best-corrected visual acuity and that seemed to be a complaint from those people who came before us today, that they didn't know about it, and if they want to know about it, I think it would make sense to put the whole table in there to be fair, and does anyone have any thoughts on that?
I mean, where I'm coming from is we had more than one person talk about the severity of the dryness they have and the point that they wish they knew and only 7.4 percent had significantly worse but 21.5 percent had worse. So you have 32 percent that had worse, and I think I personally would want to know that as a patient without being too burdensome, but I think that's important information. Dryness, glare, halos, night driving difficulty, and fluctuation of vision, all of those had approximately more than 20 percent of people in the worse or significantly worse category which is not trivial.
MR. McCARLEY: (Industry Rep) Yes, just very quickly. This is Rick McCarley.
One thing I would say is that if there are any recommendations I think that the panel would make, in general terms, regarding LASIK, I think it should be separated and then consideration should be taken by the FDA of how you're going to get that out to the rest of the companies. This dry eye issue, as far as I know, isn't inherent to this procedure that you're discussing today for this application. So this is a new issue that's industry-wide. I don't think this PMA application should be burdened with having that as, you know, a portion of their labeling while the other ones don't.
DR. WEISS: Dr. Bullimore?
DR. BULLIMORE: (FDA panel). This is Dr. Bullimore.
I welcome the opportunity we have to set a precedent, and I would also welcome the rest of the industry being asked to update their patient and physician information to reflect the current climate. So I mean, if you feel that the industry wants to come back to the FDA and update all of the physician and patient booklets, I think the panel would be generally supportive of that issue.
DR. WEISS: I can see them lining up.
DR. SWANSON: What I'm saying is in the slides that we got, there was a comparison. The postop uncorrected ??
DR. WEISS: Oh, versus the preop?
DR. SWANSON: ?? versus the preop best-corrected, what happens is half of the people are not as good after the surgery as they were with their glasses. The question of whether or not they're going to want to wear glasses or something, but that's really not communicated to the person. What are the benefits? The benefits are you have a 50-percent chance that without glasses, you'll have as good acuity as you do now.
Surgical Eyes recommends an indication that limits use to a 6.5mm pupil to match the ablation zone of this device. We believe spherical aberrations translated into patient language, night vision complaints, would be lessened by such a limitation.
DR. PETTIT: With regard to the study, the dry eye issue, if the patients had significant dry eye that could not be controlled with drops and what have you, then they were excluded from the study. I don't think we have a specific contraindication in the label to that effect at the present time.
DR. WEISS: So would that be listed in the body of the study? Would I find that in the body of the study, that the patients with significantly dry eye were excluded?
DR. PETTIT: It's actually in the protocol, and we can find exactly where that is.
DR. WEISS: So it's in the protocol, but would it be in the physician's book? Because I don't see it in the physician's book.
DR. PETTIT: I don't know.
DR. WEISS: And I think Mr. Link's question would be then addressed to why, if it was in the study, why would it not be in the physician's book?
DR. PETTIT: It should be in the physician's book.
DR. BRADLEY: Yes. I don't think it's an issue necessarily for the data in the study, but the issue has been raised today and I think everybody seems to agree that, sure, perhaps you shouldn't do this procedure on somebody with dry eye. It's just going to get worse, and there are these sort of ill-defined but widely held concerns that patients with large pupils may have some problems, and as I think somebody pointed out earlier today, this information is not adequately communicated to the patient. So the intent that I had with this suggestion is that the patient be alerted to these problems and also make sure the physician is alerted and perhaps the patient and the physician can discuss this.
DR. WEISS: But when you say large pupils, would you want to be more specific? Larger than the ablation zone or do you want to keep it at that? Keep it broad?
DR. BULLIMORE: I'd keep it broad.
DR. WEISS: So can you restate that and then maybe we can have a second? Can you just restate what your ??
DR. BULLIMORE: What did I say originally, Michael?
DR. GRIMMETT: I wasn't transcribing.
DR. BRADLEY: The preexisting dry eye condition and large nighttime pupils ??
DR. BRADLEY: And/or large nighttime pupils may decrease your satisfaction with the LASIK procedure and you should discuss this issue with your physician.
DR. BULLIMORE: I second.
DR. WEISS: Second. Can we have a vote? All those in favor, please raise your hands.
(Show of hands.)
DR. WEISS: Nine in favor. It's unanimous. That passes.
That's our FDA. Amidst unknowns, questions and concerns, the vote is unanimous.