Introduction of Issues for Excimer Laser Guidance




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DEPARTMENT OF HEALTH AND HUMAN SERVICES


FOOD AND DRUG ADMINISTRATION


CENTER FOR DEVICES AND RADIOLOGICAL HEALTH


OPHTHALMIC DEVICES PANEL


Ninety third Meeting


OPEN SESSION


Thursday, October 22, 1998


1:47 p.m.


Lincoln Ballroom

Silver Spring Holiday Inn

Silver Spring, Maryland


C O N T E N T S


AGENDA ITEM: PAGE


Call to Order

James P. McCulley, M.D., Chair 3


Introductory Remarks

Sara M. Thornton, Executive Secretary 3


Open Public Hearing 8


Presentation

Guy M. Kezirian, M.D.

CRS Clinical Research, Inc.

SurgiVision Consultants, Inc. 9


Year 2000 Date Problem Update

Thomas B. Shope, Ph.D.

Center for Devices & Radiologic Health 27


Division Update

A. Ralph Rosenthal, M.D.

Director, Division of Ophthalmic Devices 44


Branch Update

James F. Saviola, O.D.

Chief, Vitreoretinal & Extraocular Devices Branch 45


Branch Update

Morris Waxler, Ph.D.

Chief, Diagnostic & Surgical Devices Branch 51


Introduction of Issues for Excimer Laser Guidance

Discussion

Morris Waxler, Ph.D. & Malvina B. Eydelman, M.D. 54


Panel Discussion


Report of Michael W. Belin, M.D. 56

Report of Mark A. Bullimore, McOptom, Ph.D. 92

Report of Walter J. Stark, M.D. 114


Adjournment 153


P R O C E E D I N G S

Call to Order

DR. McCULLEY: I'd like to call to order the Ophthalmic Devices Panel Open Session, and at this point would like to turn the floor to Sara Thornton for introductory remarks.

Sara?

Introductory Remarks

MS. THORNTON: Good morning. I'd like to welcome the FDA staff, the public and the panel, and the panel back to the table, hopefully, after a very good lunch.

Before I proceed with today's agenda, I have a few short announcements. Messages for panel members and FDA participants, information or special needs should be directed through Ms. Ann Marie Williams or Ms. Theresa Lewis, who will be available at the registration table just outside the room.

I'd like to ask all meeting participants, panel and public to please identify yourselves before speaking clearly into the microphone. We have turned the microphones up a bit since this morning's session, and I hope that will help, but we still need your identification for the transcriber.

At this time, I'd like to extend a special welcome and introduce to the public three panel participants who have recently joined the Ophthalmic Devices Advisory Committee and are panel participants for the first time.

On my left, Dr. Michael Grimmett, panel consultant, is Associate Professor of Ophthalmology at the Bascom Palmer Eye Institute of the University of Miami School of Medicine in Miami, Florida. He is a specialist in corneal and external disease and a recognized expert on the medical/legal/ethical issues associated with refractive surgery.

Also on my left, Dr. Alice Matoba is Associate Professor of Ophthalmology at the Baylor College of Medicine in Houston, Texas and a specialist in corneal and external disease and anterior segment surgery. She is recognized internationally for her presentations on many clinical aspects of infectious corneal diseases, contact lenses, intraocular lenses and corneal transplants.

On my right, Dr. Ming Wang is an Assistant Professor of Ophthalmology and Visual Sciences at Vanderbilt University School of Medicine in Nashville, Tennessee and a corneal and external disease specialist. He holds a Ph.D. in physical chemistry and has completed postdoctoral fellowships in laser spectroscopy, molecular biology and ocular genetics. He is currently researching laser refractive surgery and the molecular biology of corneal wound healing.

To continue, will the remaining panel members please introduce themselves, beginning with Dr. Frederick Ferris?

DR. FERRIS: Dr. Frederick Ferris, Director, Division of Biometry and Epidemiology, National Eye Institute, NIH.

DR. RUBIN: Gary Rubin, Associate Professor of Ophthalmology, Wilmer Eye Institute, Baltimore.

DR. BELIN: Michael Belin, Professor of Ophthalmology, Albany Medical College.

DR. PULIDO: Jose Pulido, Professor and Head, Department of Ophthalmology, University of Illinois.

DR. HIGGINBOTHAM: Eve Higginbotham, Professor and Chair, Department of Ophthalmology, University of Maryland in Baltimore.

DR. McCULLEY: Jim McCulley, Professor and Chairman, Department of Ophthalmology, University of Texas Southwestern Medical School.

DR. SUGAR: Joel Sugar, Professor of Ophthalmology, University of Illinois at Chicago.

DR. BULLIMORE: Mark Bullimore, the number one ranked Ohio State University College of Optometry.

DR. JURKUS: Jan Jurkus, Professor of Optometry, Illinois college of Optometry in Chicago.

DR. MACSAI: Marian Macsai, Professor of Ophthalmology, West Virginia University School of Medicine.

DR. STARK: Walter Stark, Professor of Ophthalmology, Wilmer Eye Institute, Johns Hopkins.

DR. BRADLEY: Arthur Bradley, Associate Professor of Optometry and Visual Science, Indiana University.

DR. VAN METER: Woodford Van Meter, private practice of ophthalmology in Lexington, Kentucky.

MS. MORRIS: Lynn Morris, Communications Coordinator at University of California San Francisco, and I am a consumer member of the panel.

DR. YAROSS: Marcia Yaross, Director, Worldwide Regulatory Affairs at Alergan in Irvine, California, an industry representative to the panel.

MS. THORNTON: Thank you.

Also with us at the panel today is Dr. Ralph Rosenthal, who is Director of the Division of Ophthalmic Devices at FDA.

I'd like to also not that the allotted hour for the open public hearing presentation, because this is a 2 day meeting, has been split into two 30 minute periods to be held at the beginning of each day of the open session.

During the meeting today and also tomorrow, there will be opportunities for public comment interspersed with the panel discussion on particular issues that were just discussed, and the Chair, Dr. McCulley, will recognize those who wish to comment and will determine the duration of the comment period based on the time that we have for the full panel discussion and the number of people who wish to speak.

I have one more thing. I'd like to read the Conflict of Interest Statement for today's meeting. The following announcement address conflict of interest issues associated with this meeting and is made part of the record to preclude even the appearance of impropriety. To determine if any conflict existed, the agency reviewed the submitted agenda and all financial interests reported by committee participants. The conflict of interest statutes prohibit Special Government Employees from participating in matters that could affect their or their employers' financial interests. However, the agency has determined that participation of certain members and consultants, the need for whose services outweigh the potential conflict of interest involved, is in the best interest of the Government.

A waiver is on file for Dr. Michael Belin for his financial interest in firms at issue that could potentially be affected by the Committee's deliberations. The waiver allows this individual to participate fully in today's deliberations. A copy of this waiver may be obtained from the agency's Freedom of Information Office, Room 12A 25 of the Parklawn Building.

We would like to not for the record that the agency took into consideration other matters regarding Drs. Arthur Bradley, Frederick Ferris, Michael Grimmett and Janice Jurkus. These panelists reported past and current involvements in firms at issue but in matters not related to today's agenda. Since their interests are unrelated, the agency has determined that they may participate in the Committee's deliberations.

In the event that the discussions involve any other products or firms not already on the agenda for which the FDA participant has a financial interest, the participant should excuse himself or herself from such involvement, and the exclusion will be noted for the record.

With respect to all other participants, we ask in the interest of fairness that all persons making statements or presentations disclose any current or previous financial involvement with any firm whose products they may wish to comment upon.

Thank you, Dr. McCulley. I'll now turn the meeting over to you to open the open public hearing portion.

Open Public Hearing

DR. McCULLEY: We'll now begin the open public hearing. We have only one scheduled speaker. I'll remind both Dr. Kezirian as well as others who wish to speak that you have 10 minutes for presentation. The only person or people who may query the presenter are panel members and consultants at the conclusion of the presentation.

I'd like to ask Dr. Guy Kezirian to come forward and remind everyone that in your packet that was at your place today, there is a handout from Dr. Kezirian.

Presentation of Guy M. Kezirian, M.D.

CRS Clinical Research, Inc.

SurgiVision Consultants, Inc.

DR. KEZIRIAN: Thank you, Dr. McCulley. It's a great pleasure to be here before the panel once again and to have a chance to share what we have learned about LASIK in the CRS LASIK studies and to, hopefully, allow you to consider those comments in your design of your new guidelines.

[Slide.]

We in the CRS LASIK study have administered several protocols now, both IDE and non IDE studies, and we have about 250 physician participants in our overall project.

The entire project is funded by physicians  we haven't taken industry money for the studies  and it is done as an independent study of these physicians, however, with open enrollment. We allow anyone who is interested as a physician to enroll.

We are in the process of applying for PMA relabeling of the existing approvals for the lasers using our data with both the Summit and the VISX companies.

[Slide.]

One of the things that has been unusual about our study is that we have this moniker that Morris Waxler and Charles Caseberg [ph.] coined called the "PRIDE" format. The concept behind the "practical reality" IDE is to match the study with practice conventions so that examinations, examination internals and examination content, procedures and the entire design of the protocol attempt to match the standard of care practice of the procedure in the ophthalmic community.

As a result, we feel that ew are gathering information that will reflect the actual performance of the laser and of the procedure after any approval is reached with it.

[Slide.]

These are some of the elements that make up the PRIDE format that make it a little bit different than some of the conventional IDEs, and we can say without qualification that we feel that the process has been very effective and allowed us to gather a large amount of information which we feel directly reflects on how the procedure actually performs.

[Slide.]

Through that, I want to share with you some of our conclusions about LASIK and implore that you consider some of these as you create your guidelines.

We recognize that LASIK presents some increased risks and some decreased risks compared to PRK, and I have attempted to itemize them here, and I'd like to go through some of these to enumerate just how frequent they are and whether or not it's something that needs to be considered as a separate reportable event.

We found that operative complications are unusual, that despite the press surrounding keratomes, that keratome related events or any events result in less than half a percent of surgery being aborted.

We also find, having carefully tracked this, that reported intraoperative complications related to the keratome did not correlate with loss of best corrected acuity. And while that at first seems like it wouldn't make sense, it is a part of the protocol design that if any event occurs with the keratome, surgery is abandoned, the eye is allowed to heal, and surgery is reattempted at 3 months or more later on. We have found that that has been very effective in preventing intraoperative keratoma complications from causing acuity loss.

However, we found that there is a significant number of postoperative complications related to the keratome, and they are listed, with debris, interface epithelium, flap wrinkling, stain, et cetera, and they occur at an incidence of about one percent. However, we have noticed that most of these are not associated with loss of best corrected acuity and that, with treatment, they do just as well as the eyes that did not have the complications.

It is a significant event as we talk about designing guidelines, because to this date, the guidelines require that those events be qualified as adverse events, and I don't think that that is appropriate.

We were concerned, greatly concerned, at the beginning of the study about ectasia, especially in the higher refractive ranges of treatment, and we have had no ectasias occur. We have over 20,000 cases in our database at this point, and we have zero ectasias.

Now, that again is not magic. It occurs because we have depth limits. We do not permit surgery to occur within 250 microns of the endothelium, and we think that that appears to be sufficient to prevent the occurrence of ectasia.

[Slide.]

We have noticed that some of the things which plagued PRK do not exist in LASIK. We have not seen any haze in any eye beyond trace. We are finding that stability occurs very quickly in myopic LASIK. Depending on how you juggle the FDA definition of stability, that's either by one month or 3 months, depending on whether you take the second observation as being the beginning of stability or the first. In my written remarks, I expand quite a bit on those comments, and I hope you'll have a chance to look at them.

Glare and halos occur after LASIK. However, when you compare them against preoperative levels, they are less than the preoperative level with glasses or contacts. We found that very interesting, because in the current guidelines and in the current PMA charts, it asks for postoperative glare, halos and other patient symptoms and doesn't ask you to compare them to preoperative levels. And I think that taking them out of context unfairly suggests that the procedure is causing those symptoms, when we find it actually improves them compared with preoperative levels.

[Slide.]

So in the creation of your guidelines, I would suggest that we have learned enough about LASIK to allow us to eliminate some of the more tedious aspects of doing IDEs and that, since the procedure will be performed with a given standard of care after it is released, that we attempt to make those findings that we make during the IDE process correlate with those observations which are made by surgeons after approval. It allows us to make one to one comparisons and not have to extrapolate and translate data that occur under different conditions.

We have found that 6 month follow up gives us useful information, well enough to establish stability and well enough to evaluate for adverse events and complications, and we think that 6 months is enough for myopic LASIK procedures in terms of follow up, and we think that the basic observations that are made clinically are very descriptive about events that occur. We have not had a hidden group reported to us of problems with patients that haven't been reflected in vision refraction, best corrected acuity or the patient questionnaire. Those tests are sufficiently sensitive to pick up complications when they occur.

I would suggest  and this has been a great discussion in some of the Eye Care Technology Forum meetings  that we try to come up with a common denominator for safety and that in these procedures, not exclusively but for the most part, best corrected acuity loss is sufficient; that keratome flap lifts, keratome epithelial ingrowth that is cleaned, and other things that occur should not be rated as adverse events if they are not accompanied by best corrected acuity loss; and that aborted surgery per se should not be listed as a complication unless it is accompanied by a loss of best corrected acuity. We have found that it hasn't been.

[Slide.]

I would further suggest that the other events which occur related to keratomes be tracked sort of as a sub study within the IDE. If studies allow the use of multiple keratomes, track it; look at safety issues and rank them by keratomes. But don't limit studies to one keratome, because you aren't going to find out how that device or that procedure works when it is released and is done with multiple keratomes. And if you track it as an independent variable, you can look at the keratome as a separate issue.

[Slide.]

And for efficacy, at least with myopic results, 6 months seem to be adequate, and that we don't know the answer yet with hyperopia, and our own studies are going out at least to a year and some of them to two, because we feel like hyperopia is more likely to experience regression and refractive change. Myopia, we have not experienced that, and I think that that might be considered as you design your new guidelines.

[Slide.]

Much more extensive written remarks are available at the front desk, and I have passed them out to the panel members, if you care to venture deeper into some of our experiences and learn more about what we have done.

I can also be contacted on line or at CRS, and I would welcome any inquiries that you have.

Thanks very much.

DR. McCULLEY: Thank you very much.

I would commend to each of you to take the opportunity to read the handout that Dr. Kezirian has provided to us. I had the opportunity to read it and found it interesting and useful.

Are there questions or comments from the panel for Dr. Kezirian?

Dr. Stark?

DR. STARK: Congratulations on such large numbers. I would like to know how you ensure that every patient who is entered into the study that should be  for example, is there a chance that some of the investigators could exclude complications right off the bat? And then, what is your follow up rate on these patients? Which patients would fall into the 12 month period, and what percentage of them have follow up?

DR. KEZIRIAN: The protocol establishes entry guidelines just like any protocol, and we have the criteria specified. They do exclude at this point prior corneal surgery and that sort of thing, so is our experience different from how the procedure might perform when it is being done without those filters, bringing people in  perhaps. But I think that that's not inconsistent with what you will be establishing in the guidelines, because the guidelines do the same thing. We know, for example, that surface PRK is done in eyes which weren't studied under the protocols as a practice of medicine issue. I don't see a conflict there; I think that's okay.

The way that we report is on line, and we use the Datasite system. Once a patient does in, he can't be removed or changed out of the protocol. And we require the reporting of the eyes to be done within 48 hours of the event, whether that was surgery or postoperative exam. So we have a good count as to how many patients are enrolled.

We have, as you noticed, a lot of different protocols, and the IDE protocols are the ones that we police the most and the ones I have good data on follow up with, and we have, again, a practical reality way of dealing with this, in that if an investigator becomes noncompliant in follow up, we don't allow him to submit any more eyes.

So with that very simple carrot and stick, we are able to keep compliance pretty high, and we run  and any snapshot, of course is different  we just finished our approved range IDE, and we are just finishing some of our other IDEs, and depending on exactly what protocol, it ranges between 75 and 90 percent. So it depends  it's a complicated question  but overall, we feel we have been pretty successful in getting the follow up in.

DR. McCULLEY: Dr. Wang?

DR. WANG: As an elective procedure, it is extremely important in my opinion to be safe and also to ensure patient satisfaction. I agree with you the best corrected visual acuity is one of the most important parameters. You did say "seldom." Do you know, among the 20,000 patients, what percentage have actually lost best corrected visual acuity?

DR. KEZIRIAN: I wish I had brought my recent annual report with me so I could give you the exact number. But I know that when you stratify the results according to preoperative refractive error, and when you consider 2 lines or greater as being outside the safety zone, we have shown safety through 12 D with both lasers. We have had less than the FDA limits on best corrected acuity loss through 12 D.

DR. McCULLEY: Dr. Matoba?

DR. MATOBA: Did you have any postoperative infections?

DR. KEZIRIAN: We haven't had any postoperative infections occur yet. Now that you've said it, one will happen tomorrow, but we haven't had any yet.

DR. McCULLEY: Other questions?

[No response.]

DR. McCULLEY: I'd like to clarify a point with the FDA, if I may. The charge to us for this afternoon's session is to address the three issues that you have posed to us with the specific preassignments as opening presentations, and not for us to review the entire guidance document.

DR. ROSENTHAL: That's correct. We'd like you to emphasize the three. I think Morris has a fourth one. There is actually a fourth one on stability. But that doesn't mean you can't make comments on issues that you think are of particular import.

DR. McCULLEY: Well, the approach is  we can either target, or if the charge to us  I don't think any of us came prepared to redo the entire guidance document, and I think that's almost a dangerous route to go down. So we can make comments for you if you want.

DR. ROSENTHAL: Well, if somebody feels particularly strong about an issue in the guidance document, we'd certainly like to hear it.

DR. McCULLEY: Okay. Dr. Kezirian has brought up a number of points that my expectation would be that we would not address or necessarily discuss; that you can take his comments under advisement  

DR. ROSENTHAL: That's right.

DR. McCULLEY:   but the panel is not prepared to or expected to either agree or disagree with many of the other issues in the guidance document that could be addressed; that we are going to concentrate on the three, and if there is a fourth, then a fourth.

DR. ROSENTHAL: That's correct.

DR. STARK: Jim, could I ask one more question?

DR. McCULLEY: Yes. Dr. Stark.

DR. STARK: I remember the presentation by Drs. Waring and Stulting on their submission, and the presentation at scientific meetings indicated about a 10 percent epithelial ingrowth rate, and some of that might have been talked about innocuous. Could you give us what is reported as the epithelial ingrowth rate for the 20,000 or however many cases you are following, and also, is there any independent validating of results, review of charts, or is it just all left up to the investigator? For example, if someone had some complications and decided not to report them, are we assured that you are getting the complications reported?

DR. KEZIRIAN: Two separate questions. I can't report on the 20,000 for epithelial ingrowth. I can report on 5, because those are the ones that are done in the IDE studies which we just recently crunched. And the epithelial ingrowth rate is nowhere near 10 percent. It is in the 2 percent range.

There is the distinction that we make in epithelial ingrowth that is something requiring treatment or not; sometimes, there is a small nest [ph.] that the surgeon will decide to just leave, and that incidence is about 2 percent, that requires some sort of treatment or intervention.

I would emphasize, though, that those events do not necessarily result in loss of vision, and in fact, they are infrequently associated with loss of vision; that they can be successfully treated.

As far as the independent validation of data goes, the answer is yes and no. The "yes" part is that the investigators are required to maintain a separate file from the chart of the source documents and the report forms, and that we have on five or six different occasions sent out lists looking for the source forms to be submitted as well as the report documents, so that we then take and compare those two. So we do have that going on. We do visit all the sites at the beginning of the study and intermittently during the study, and we have done some of that.

But I think what is most encouraging for us and most reassuring to us is that we hold meetings several times a year, and complications are a major focus of the meeting, and we almost have a zeal to present complications because they often spark very interesting discussions. I don't think people are trying to hide complications, but have we gone and checked every chart  the answer is on.

DR. McCULLEY: Let me remind everyone that we have limited time, so the longer the question, the longer the answer, and the fewer questions and issues we are going to be able to address.

Dr. Bradley?

DR. BRADLEY: Your Item 4 in the written documents that you provided is essentially the issue of cycloplegic refractions, and you raise the issue of the dilated pupil that comes along with the cycloplegia, and you are suggesting that these evaluations should be done with an artificial pupil of maybe 3.5 mm placed i front of the eye.

I think that given the number of reported subjective complications from patients occurring primarily at night and the one report that I know of from Germany of patients  in that case, I think it was PRK  who were failing their night driving tests and the optical expectation of halos with a large pupil and the obvious implications for retinal image quality, I think it would be important to keep on top of the impact of a large pupil which is going to occur under low light conditions with these patients and not simply record the result that you obtained with the small pupil, because that would in essence be the best case scenario. The worst case scenario, which is often driving patients, the one that we are most concerned about, should also be recorded.

So I think it is worth taking data with a large pupil.

DR. KEZIRIAN: Well, I agree and disagree. I think that the subject patient question captures some of that information, and if what you are looking for is large pupil vision, I think that should be tracked separately and shouldn't be called a cycloplegic exam, because you are introducing a lot of things when you dilate the pupil.

So if you want to have a nonrefractive exam where you do cycloplegic for some reason, I think a mask is appropriate; and if you want to capture information about what happens when you dilate the pupil, that's another exam. it's not inappropriate to do  I don't think it has to be done in everyone.

Dr. Rubin has presented a very nice exam to look at post refractive surgery, post excimer procedure vision, and it includes low contrast measurements of vision in dim light and bright conditions, and I think that it might be appropriate to require some of those measurements to be made, but I don't think those are going to be so variable on the patient. I do think those are going to be features that correlate best with the prophylometry of the ablation. They are going to be laser characteristics. Those are going to be ablation characteristics that determine that, and that could probably be measured just as well in lab as it could be in a patient  and probably more reliably.

So I think that less is more when it comes to some of these clinical studies. If you have a patient requirement be cyclopleged at 3 months, half of them won't show up because they don't want to do that.

DR. McCULLEY: Part of my motivation before in saying what I did  Dr. Kezirian has basically gone through and made comment on many, many things in the guidance document, and I don't think that it should be our role now to either agree or disagree or try to argue those points. We don't have the time. There are things in here that I agree with, there are things that I disagree with. And I think what I would say to the FDA is don't take our silence as being concurrence with everything that is in his very fine document. And I don't think our role here is to try to reach consensus relative to all of the issues that Dr. Kezirian brought up. It is food for thought, and I would hope you would take it that way, and I think that's what we should take it as  not necessarily to reach consensus on the many, many, many items that he brought up in his document.

DR. KEZIRIAN: And that's the spirit in which it was offered  

DR. McCULLEY: And we appreciate it.

DR. KEZIRIAN:   and I am happy to give you the last word and step down at this point.

Thank you very much for your attention.

DR. McCULLEY: Well, I think there were two other questions that I had seen coming  and I took it as that, and my comments were not necessarily directed at you.

Dr. Belin?

DR. BELIN: Mine is a comment, not a question. I don't expect a response, and I'll just give you a differing opinion that I disagree that flap complications or aborted surgery is not a complication.

I think an aborted surgery is an ultimate complication. It may not be an adverse event in that it doesn't lead eventually to patient morbidity, but it is a complication.

DR. KEZIRIAN: I'll agree with that.

DR. BELIN; I think that if we were to look at a laser, and if the laser failed 20 percent of the time when we expected to do surgery, that would not be acceptable.

If you go in with the intention of completing surgery, and you do not complete it, that's a complication.

DR. McCULLEY: Dr. Ferris?

DR. FERRIS: Two comments. One, my view is that a patient views another surgery as an adverse event even if the vision is still good at the end of the day, because to him or her, that means an additional procedure.

The second thing is just a question or a point of clarification. You don't like the term "best spectacle corrected visual acuity." In epidemiologic studies, we have differentiated "best spectacle corrected" from "spectacle corrected" to try to make it clear that it wasn't the glasses you were walking around with but in fact the best corrected. Spectacle correction to me means what you are walking around with  you come into the office and read the chart with the glasses that you own, which may or may not be appropriate. I think that's the reason for the difference in those two terms.

If there is something else, I think you should make it clear, because it's not clear to me.

DR. McCULLEY: Other questions, comments?

[No response.]

DR. McCULLEY: Thank you very much. We'll now let you escape.

DR. KEZIRIAN: Thank you very much.

DR. McCULLEY: Are there any others in the audience who wish to come to the podium to make comments?

[No response.]

DR. McCULLEY: Seeing none, we will now close the open session.

The next item on our agenda is a Year 2000 Date Problem Update, to be presented by Dr. Thomas Shope.

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