FOOD AND DRUG ADMINISTRATION

 

CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

 

OPHTHALMIC DEVICES PANEL

 

107TH MEETING

 

THURSDAY,

FEBRUARY 5, 2004

 

      The Panel met at 9:00 a.m. in Salons B-D of the Gaithersburg Marriott Washingtonian Center, 9751 Washingtonian Boulevard, Gaithersburg, Maryland, Jayne S. Weiss, M.D., Chair, presiding.

 

PRESENT:

JAYNE S. WEISS, M.D., Chair

ARTHUR BRADLEY, Ph.D., Voting Member

ANNE L. COLEMAN, M.D., Ph.D., Voting Member

MICHAEL R. GRIMMETT, M.D., Voting Member

WILLIAM D. MATHERS, M.D., Voting Member

TIMOTHY T. McMAHON, O.D., F.A.A.O., Voting Member

KAREN BANDEEN-ROCHE, Ph.D., Consultant

RICHARD CASEY, M.D., Consultant

ANDREW J. HUANG, M.D., M.P.H., Consultant

MARIAN S. MACSAI-KAPLAN, M.D., Consultant

OLIVER D. SCHEIN, M.D., M.P.H., Consultant

JANINE A. SMITH, M.D., Consultant

WOODFORD S. VAN METER, M.D., Consultant

GLENDA V. SUCH, M.Ed., Consumer Representative

ANDREW K. BALO, Acting Industry Representative

SARA M. THORNTON, Executive Secretary

 

FDA REPRESENTATIVES:

EVERETTE T. BEERS, Ph.D.

GERRY W. GRAY, Ph.D.

BERNARD P. LEPRI,, O.D., M.S., M.Ed.

DONNA R. LOCHNER

JEFFREY TOY, Ph.D.

A. RALPH ROSENTHAL, M.D.

 

 

 

SPONSOR REPRESENTATIVES:

RICK McCARLEY

STAN BENTOW, Ph.D.

R. DOYLE STULTING, M.D., Ph.D

VANCE THOMPSON, M.D.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


                    A-G-E-N-D-A

 

Call to Order, Jayne S. Weiss, M.D., Chair...... 5

 

Sara M. Thornton, Executive Secretary

      Introductory Remarks...................... 5

      Conflict of Interest Statement............ 8

      Appointment to Temporary Voting Status... 11

 

OPEN PUBLIC HEARING............................ 12

 

OPEN COMMITTEE SESSION, Jayne S. Weiss, M.D., Chair

 

DIVISION UPDATE

 

A. Ralph Rosenthal, M.D., Director............. 40

 

BRANCH UPDATES

 

Donna R. Lochner, Chief, Intraocular and Corneal Implants Branch   41

 

Everette T. Beers, Ph.D., Chief, Diagnostic and Surgical Devices Branch 42

 

PMA P030028

 

SPONSOR PRESENTATION

 

ARTISAN Myopia Phakic Intraocular Lens......... 44

 

Panel Questions for the Sponsor................ 77

 

FDA PRESENTATION

 

Jeffrey Toy, Ph.D., Team Leader............... 108

Bernard Lepri, O.D., M.S., M.Ed, Clinical

Reviewer...................................... 109

Gerry W. Gray, Ph.D., Statistician............ 116

 

LUNCH

 

 

 

COMMITTEE DELIBERATIONS

 

Panel Questions for FDA....................... 151

 

Primary Panel Reviews:

 

Dr. William D. Mathers........................ 158

Dr. Oliver D. Schein.......................... 168

Dr. Marian S. Macsai-Kaplan................... 179

 

PANEL DISCUSSION OF PMA P030028

to include FDA questions to the Panel......... 189

 

30-MINUTE OPEN PUBLIC HEARING SESSION......... 303

 

FDA - CLOSING COMMENTS

 

SPONSOR - CLOSING COMMENTS.................... 307

 

Voting Options Read........................... 310

 

PANEL RECOMMENDATION TAKEN BY VOTE............ 316

 

POLLING OF PANEL VOTES........................ 344

 

COMMENTS FROM CONSUMER AND INDUSTRY

REPRESENTATIVES............................... 350

 

FINAL PANEL COMMENTS.......................... 352

 

OPEN MEETING ADJOURNED

 

 

 

 

 

 

 

 

 

 

 

 

 


               P-R-O-C-E-E-D-I-N-G-S

                                         9:01 a.m.

            DR. WEISS:  I'm going to ask everyone to take their seat, please.  We'll be starting shortly.  I would like to call this meeting of the Ophthalmic Devices Panel to order and note that there is a quorum present.  We will have introductory remarks by Sally Thornton.

            MS. THORNTON:  Good morning.  Permit me to introduce myself.  I'm Sara Thornton, Executive Secretary for the panel.  On behalf of the FDA I would like to welcome you to the 107th meeting of the Ophthalmic Devices Panel.

            Before we proceed with today's agenda, I have a few short announcements to make.  First of all, I would like to remind everyone to please sign in on the attendance sheet on the registration area just outside the meeting room here.  All public handouts for today's meeting are available at the registration table. 

            Messages for panel members and FDA participants, information, or special needs should be directed through Ms. AnnMarie Williams who is available at the registration area.  The phone number for calls to the meeting area is (301) 590-0044.

            In consideration of the panel, the sponsor and the Agency, we ask that those of you with cell phones and pagers either turn them off or put them on vibration mode while in this room and to make your calls, please, outside the meeting area.  Note the flyers on the door.

            Lastly, will all meeting participants please speak directly into the microphone and give your name clearly so that the transcriber will have an accurate recording of your comments.

            Now, at this time I would like to announce the voting member appointment of Dr. William Mathers of the Casey Eye Institute in Portland, Oregon.  Dr. Mathers has been appointed to serve until October 31st of 2007.

            I would like to welcome our Acting Industry Representative, Mr. Andrew Balo, Vice President for Regulatory and Clinical Affairs with DEXCOM, Inc. in San Diego, California.  Mr. Balo also serves as the Industry Representative on the Neurological Devices Panel.  Mr. Balo is sitting in for our panel Industry Representative Mr. Ronald McCarley who has recused himself from today's panel deliberations.

            Will the remaining panel members please introduce themselves beginning with Glenda.

            MS. SUCH:  Glenda Such, Lighthouse International, Consumer Representative.

            MR. BALO:  Andy Balo, Industry Representative.

            DR. SCHEIN:  Oliver Schein, Wilmer Eye Institute, Johns Hopkins.

            DR. BANDEEN-ROCHE:  Karen Bandeen-Roche, Department of Biostatistics, Johns Hopkins.

            DR. McMAHON:  Timothy McMahon, Department of Ophthalmology, University of Illinois at Chicago.

            DR. BRADLEY:  Arthur Bradley, School of Optometry, Indiana University.

            DR. MACSAI:  Marian Macsai, Evanston Northwestern Healthcare, Northwestern University.

            DR. GRIMMETT:  Michael Grimmett, the Bascom Palmer Eye Institute, the University of Miami.

            DR. WEISS:  Jayne Weiss, Kresge Eye Institute, Wayne State University School of Medicine.

            DR. MATHERS:  Bill Mathers, Oregon Health Sciences University.

            DR. CASEY:  Richard Casey, Charles Drew University, Jules Stein Eye Institute, Los Angeles.

            DR. COLEMAN:  Anne Coleman, Jules Stein Eye Institute, UCLA.

            DR. VAN METER:  Woody Van Meter, the University of Kentucky in Lexington.

            DR. HUANG:  Andrew Huang, University of Minnesota.

            DR. ROSENTHAL:  Ralph Rosenthal, Division of Ophthalmic and ENT Devices, FDA.

            MS. THORNTON:  I'd like to just announce that Dr. Janine Smith who will be in attendance at the panel will be here in a very short time.

            I'd like to now read the conflict of interest statement for the meeting on February 5, 2004.  The following announcement addresses conflict of interest issues associated with this meeting and is made part of the record to preclude even the appearance of an impropriety.

            To determine if any conflict existed, the Agency reviewed the submitted agenda for this meeting and all financial interest reported by the committee participants.  The conflict of interest statutes prohibit special government employees from participating in matter that could affect their or their employer's financial interest.

            The Agency has determined, however, that the participation of certain members and consultants, the need for whose services outweighs the potential conflict of interest involved, is in the best interest of the government.  Therefore, waivers have been granted for Drs. Michael Grimmett, Oliver Schein, and Woodford Van Meter for their interest in firms that could potentially be affected by the panel's recommendations.

            Dr. Grimmett's waiver involves an imputed interest, a grant to his institution for the sponsor study in which he has no involvement and is uncompensated.  Dr. Oliver Schein's waiver involves two consulting arrangements, one pending for a competitor's unrelated device for which he has not received any compensation, and the second with a competitor's unrelated device for which he receives an annual fee between $10,000 and $50,000.  Dr. Van Meter's waiver involves an imputed interest, a stockholding in the parent of a competing technology firm in which the value is greater than $100,000.

            The waivers allow these individuals to participate fully in today's deliberations.  Copies of these waivers may be obtained from the Agency's Freedom of Information Office, Room 12A15 of the Parklawn Building.  We would like to note for the record that the Agency took into consideration other matters regarding Drs. Anne Coleman, Arthur Bradley, Michael Grimmett, Andrew Huang, Marian Macsai, Oliver Schein, and Jayne Weiss.

            Each of these panelists reported past or current interest involving firms at issue but in matters that are not related to today's agenda.  The Agency has determined, therefore, that the panelists may participate fully in all discussions.

            In the event that the discussions involve any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participant should excuse him 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.

            I would like to now read the appointment to temporary voting status.  Pursuant to the authority granted under the Medical Devices Advisory Committee Charter dated October 27, 1990, and as amended August 18, 1999, I appoint the following individuals as voting members of the Ophthalmic Devices Panel for this meeting on February 5/6, 2004.

            Karen Bandeen-Roche, Ph.D., Richard Casey, M.D., Marian S. Macsai-Kaplan, M.D., Oliver Schein, M.D., Andrew Huang, M.D., Janine Smith, M.D., Woodward Van Meter, M.D.

            For the record, these individuals are special government employees and consultants to this panel or other panels under the Medical Devices Advisory Committee.  They have undergone the customary conflict of interest review and have reviewed the material to be considered at this meeting.  Signed, David W. Feigal, Jr., M.D., MPH, Director, Center for Devices and Radiological Health.  Dated January 20, 2004.

            Thank you, Dr. Weiss.

            DR. WEISS:  Thank you, Sally.

            We will now open the open public hearing.  I will read a statement which was requested by the FDA. 

            "Both the Food and Drug Administration and the public believe in a transparent process for information gathering and decision making.  To ensure such transparency of the open public hearing session of the Advisory Committee, FDA believes that it is important to understand the context of an individual's presentation. 

            For this reason, the FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement to advise the committee of any financial relationship that you may have with the sponsor, its product and, if known, its direct competitors.

            For example, this financial information may include the sponsor's payment of your travel, lodging, or other expenses in connection with your attendance at the meeting.  Likewise, the FDA encourages you at the beginning of your statement to advise the committee if you do not have such financial relationships.  If you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking."

            I would call Glenn Hagele to the podium as the first public speaker.  You have up to 10 minutes.

            MR. HAGELE:  I need some assistance with the video.  Dr. Weiss, with your permission, could I come after the following speaker?

            DR. WEISS:  Why don't you stay up there if they can arrange that, Mr. Hagele, because we have a written letter from someone and perhaps we can use this window of time to read the letter while you're preparing your --

            MR. HAGELE:  Thank you.

            DR. WEISS:  If that would be agreeable.

            Sally Thornton has a letter that was sent in from someone who wanted to participate in the open public hearing but was not able to appear.

            MS. THORNTON:  This is a letter from Peter D. Van Patten, M.D., the Duluth Clinic Virginia in Virginia, Minnesota. 

            "Dear Ms. Thornton.  I had planned to make a short presentation at today's meeting but could not attend due to a scheduling conflict.  If possible I would like to have my following comments read into the record during the appropriate time slot of the meeting.

            My name is Peter D. Van Patten.  I have practiced ophthalmology since 1991.  I am also a subject in the U.S. clinical study of the ARTISAN Myopia Lens and have bilateral ARTISAN implants.  I have no financial interest in the ARTISAN lens or Ophtec, the sponsor of this study. 

            The purpose of my testimony is to provide additional information to the FDA and the FDA panel for consideration during today's discussions.  Prior to receiving ARTISAN lenses my refractions were -10.0 X -0.75 in both eyes.  Previously I was having increasing problems with contact lens wear to the point where the symptoms became intolerable. 

            After considering all available options, I decided to proceed with the ARTISAN lens implant.  My left eye received the ARTISAN lens in February '99, five years ago, and my right eye received the lens in March 2001, nearly three years ago. 

            My current refractions are -0.75 X -0.5 in the left eye and plano X -0.5 in the right eye.  I have an uncorrected acuity of 20/30 in the left eye correctable to 20/20 and 20/20 uncorrected vision in the right eye correctable to 20/15.  My outcomes were very successful and my overall vision is excellent. 

            I typically wear glasses only for night driving.  I have experienced mild night glare on occasion postoperatively that was not present prior to receiving the lenses.  However, I would rate the level of glare as minimal. 

            I have had significant functional improvements during my high visual demand activities such as ophthalmic surgery.  Also, I would rate my daytime vision as suburb.  I consider both procedures to be a success.  Over the past five years I have continued to discuss the ARTISAN lens as an important investigational surgical option with my patients whom I found to be appropriate candidates for open ARTISAN lens clinical trials.

            Based on my experience as a subject in this study, it is my opinion that the ARTISAN lens is a safe and effective lens when implants by a skilled surgeon.  I would ask that you consider my comments during your discussions and hope that you are able to make a favorable recommendation today so as to make this technology available to others who seek correction for high myopia.  Sincerely, Peter D. Van Patten, M.D."

            DR. WEISS:  Thank you, Sally.

            Mr. Hagele, are you ready?

            MR. HAGELE:  We are coming up momentarily.

            DR. WEISS:  Sounds good.  If you're still having difficulty, I understand that Ms. Woodlock does not have slides so she perhaps could do her presentation while you are getting that ready.

            MR. HAGELE:  Thank you.

            DR. WEISS:  Ms. Woodlock.  Would you mind, perhaps, giving your presentation from the table instead?  Thank you.

            MS. WOODLOCK:  I am Leslie Woodlock, Patient Advocate of the Surgical Eyes Foundation. We are a nonprofit organization whose constituency is consumers with sub‑optimal outcomes from refractive surgery. Our goals are simply to raise awareness of the risks of elective eye surgery, provide support and identify solutions for patients living with complications, and advocate for informed decision making. I personally became involved with the Surgical Eyes Foundation after failed LASIK surgery in 2000.

            I am here today to discuss the safety of phakic lOLs. While much of SEF's concern with the ICL was discussed at this panel's meeting on October 3, 2003, we would like the panel to address the following issues:

            Diameter selection is critical for centration of this device since under sizing could result in a failure of the lens to vault the anterior capsule properly, resulting in contact of the device with the capsule and subsequent anterior cortical cataract development.

            The need for a tight fit is recognized by the applicant and yet selection of the ICL diameter is to be based on the white‑to‑white measurement. Since no exacting correlation between the white‑to‑white measurement and the ciliary sulcus diameter exists, how will patients be protected from secondary cataract development?

            The increasing thickness of the physiologic lens with aging as well as during accommodation means that the desired post‑operative vault of the ICL will fluctuate and actually diminish over time. This has the potential to accelerate the development of anterior cortical cataracts.

            The incidence of endothelial cell loss is a repeated concern throughout the previous discussion. In the event that the ICL must be removed following a noted progression of anterior capsular opacities, there is no evidence suggesting that explantation of the ICL will be less harmful to the endothelium than its continued presence.

            Further, in cases of either device‑induced or naturally occurring cataracts, the ICL will have to be explanted before the implantation of a pseudophakic IOL. Clearly, for all patients, a second and possibly third intraocular procedure must be entertained with further potential for loss of endothelial cells.

            Continuing with our concern for loss of a functional endothelium, the dynamics of a shallow anterior chamber depth and progressive endothelial cell loss is unknown at this time. Most cases of Fuchs' endothelial dystrophy do not become clinically evident until patients are approaching their fifth decade. Will implantation of the ICL result in an even earlier loss of endothelial integrity and, ultimately, penetrating keratoplasty?

            These patients would appear to be at even higher risk for endothelial cell loss regardless of an allowable standard for minimal anterior chamber depth of 2.8 or 3 mm. It is not possible to assess risk for younger individuals at the time the ICL is implanted since they will not have visible indications for the condition.

            Revisiting the effects of aging of the physiologic lens, another consequence is the shallowing of anterior chamber. The applicant has found a correlation of shallow anterior chamber depth to endothelial cell loss. It is reasonable to suspect that aging of the crystalline lens and subsequent reduction of the anterior chamber depth will put older patients at increased risk for decompensation of their corneas secondary to endothelial dystrophy.

            In regard to implantation of this device, typically the risk of cystoid macular edema increases with each intraocular surgical procedure. In the case of device‑induced cataracts with subsequent explantation followed by implantation of a pseudophakic IOL, the potential for CME would be significantly greater.

            Correct positioning of the ICL requires a tight sulcus to sulcus fit with anterior displacement of the iris. The fact that the potential narrowing of the anterior chamber angles following implantation was not consistently examined via gonioscopy in the PMA suggests only a cursory concern with the potential for narrow angle glaucoma. Patients with naturally narrow anterior chamber angles as well as those whose angles will narrow subsequent to aging, are at higher risk for development of glaucoma.

            The presence of the ICL vaulting above the anterior capsule changes the dynamic of the posterior iris and its contact with the anterior capsule. The potential for pigment dispersion is very real as the ICL haptics rub against the posterior iris.

            Pigment dispersion has a known occurrence in the general population but does not manifest until the fifth decade. Implantation of this device in younger patients with a predilection for pigment dispersion will quite conceivably accelerate the process and lead to pigmentary glaucoma.

            Anterior cortical cataracts, narrow angle glaucoma, pigmentary glaucoma and endothelial dystrophy are naturally occurring conditions but are potential complications of the ICL. A very real possibility exists that health insurers will not cover the cost of treatment for these conditions since they could be viewed as secondary to an elective procedure.

            SEF is already aware of patients receiving corneal transplants following corneal refractive surgery who were denied reimbursement by their health insurer for this very reason. The negative impact on the patient is two fold. Either they will be denied coverage for a naturally occurring medical condition or they will have to pay for the deniable complications secondary to an elective surgery.

            The optical diameter of the ICL is listed as 4.65 to 5.5 mm. While the diameter of a posterior chamber ICL cannot be compared to the typical, stated ablation diameters of LASIK and PRK, it is interesting that the optical diameter is so small. Pseudophakic lOLs are typically in the 6.0 mm range and there are still patients who will notice glare and halos under low light conditions.

            Using our knowledge of pseudophakics' experience as a guide and, given that the population having ICL surgery would typically be much younger with larger pupils, it would seem very certain that many individuals will experience unwanted glare and haloes from spherical aberrations created by the uncorrected rays of light passing through the peripheral physiologic lens.

            Continuing on with the discussion of the optical diameter effects, it is necessary to mention the recent publication of Dr. Steven C. Schallhorn's study suggesting the irrelevance of pupil size to visual quality under mesopic and scotopic light conditions, in particular, that pupil size does not correlate with night driving performance.

            This oft touted study, however, does nothing to explain why numerous journal articles by leading refractive surgeons suggest the use of brimonidine tartrate (Alphagan), an adrenergic agonist that suppresses pupil dilation to produce a relative miosis, as well the direct‑acting miotic, pilocarpine, be used post‑operatively to suppress the ill‑effects of night time driving in refractive surgery patients.         The Surgical Eyes Foundation bulletin board is overflowing with empirical evidence from our patients and our participating doctors of the effectiveness of pupil constricting agents in the reduction of low light glare and halos. Our bulletin board already has one ICL patient complaining of this very thing and two well‑known refractive surgeons recommended Alphagan as the remedy.

            With regard to quality of vision, we ask that PMAs for all forms of vision correction devices be stratified by pupil size. The PDA should mandate that quality of vision be measured objectively with wavefront and other objective tests that have been utilized by optical scientists like Dr. Raymond Applegate that stratify results by pupil size, and that these results be published and made readily available to consumers with regard to any form of vision correction device.

            We have had many patients of all ages with large pupils post on our bulletin board about nighttime visual aberrations, regardless of refractive error. We understand that an effective optical zone on the corneal surface and the optic diameter of a lens that sits behind the iris are not comparable; however, we feel very strongly that patients with large pupils are at risk with this device.

            One common experience of patients visiting our web site and bulletin board is in regards to the informed consent agreement. While explanations of potential visual and physiological complications are discussed, patients typically do not understand the chronic and irreversible nature of those complications.

            Informed consent continues to be a major concern of SEF for elective refractive surgery. Unnatural visual effects seem to impact deeply on many patients sense of well being. The psychological emotional aspects of vision complications are not something potential patients can understand or be prepared to accept following negative outcomes.

            This completes my presentation.  On behalf of the board of trustees of the Surgical Eyes Foundation and our constituency, I wish to thank the Advisory Panel for the opportunity to express our concerns.  Thank you very much.

            DR. WEISS:  Thank you very much.

            And you will be limited to 10 minutes for your presentation.

            MR. HAGELE:  That should be more than adequate.  Good morning and thank you for the opportunity to address this panel. My name is Glenn Hagele. I am the Executive Director and founder of the Council for Refractive Surgery Quality Assurance, which from this point forward I will refer to by its acronym CRSQA.

            In the way of disclaimer, I have no financial interest in AMO or the ARTISAN phakic intraocular lens. My travel here today is self‑funded. Although I am the Executive Director of CRSQA, the opinions I express are my own and do not necessarily represent the opinions of individuals affiliated with CRSQA.

            CRSQA is a nonprofit consumer/patient organization that through its sister websites USAeyes.org and ComplicatedEyes.org receives over 800,000 visitors annually. We provide objective information about refractive surgery issues and resources for those unfortunate few who have encountered a poor refractive surgery outcome.       Additionally, CRSQA evaluates and certifies refractive surgeons based upon patient outcomes.

In addition to research of published studies and case reports, my interaction with patients provides me with a unique accumulation of anecdotal information and a perspective of a patient. The issues and concerns I will raise today all relate to communication between physician and patient.

            Potential refractive surgery patients, especially high myopes and high hyperopes, seek options. With a greater understanding of the advantages and limitations of corneal‑based refractive surgery, those with high refractive errors find the probability of achieving the convenience of a reduction of the need for corrective lenses less than spectacular.

            The phakic intraocular lens has been available outside the United States for the better part of a decade, and it is reassuring that this panel will have the opportunity to determine if a new option will be available to Americans.

            Not surprisingly, I have some concerns. I will leave to others to debate clinical data, and raise only those issue that from a patient perspective are of equal importance.

            Pupil Size.  Capt. Steven Schallhorn, MD of the United States Navy recently presented a significant performance‑based task study of 105 consecutive LASIK subjects to determine what effect preoperative scotopic pupil size has on postoperative night vision.

            Dr. Schallhorn's, and subsequent studies, found no direct correlation between scotopic pupil size and reaction‑based visual task performance. Although Dr. Schallhorn's study may

provide evidence that pupil size alone is a poor predictor of induced night vision problems, I have never heard Dr. Schallhorn say pupil size is not important.

            Pupil size may be a poor predictor of night vision problems, but as any doctor who has prescribed pilocarpine or Alphagan can attest, pupil size is the moderator of night vision problems, when they exist. Although these are two very separate issues, I ask that this panel be mindful of their interrelation.

            Furthermore, the corneal‑based LASIK procedure is not an intraocular lens. Even further, it is not a phakic intraocular lens. Decades of intraocular lens development have shown the importance of edge design and pupil size in regard to halos, starbursts, and glare in low illumination environments. It seems unreasonable to disregard this body of knowledge, regardless of the conclusions of Dr. Schallhorn's findings.

            Should this panel ultimately decide to approve the device presented today, I respectfully ask the panel to consider including in the labeling for both physician and patient that the probability of induced night vision problems when the scotopic pupil is larger than the size of the full optical correction of the device is not easily determined.

            I respectfully ask that the patient labeling include a representation of these effects and explanation of probable limitations on the patient, including difficulty driving at night and reading in low illumination environments.

            Learning Curve.  Today you will have the advantage of evaluating the safety and efficacy of the proposed device when care is provided by what can only be described as some of the best surgeons in the world. I submit that if this device is approved, it will be utilized by doctors who are, shall we say, of somewhat lesser distinction.

            With reports of as much as 20% incidence of anterior sub‑capsular opacities with the first few patients of other intraocular lenses when implanted by novice surgeons, it appears self evident that proper implantation of an phakic intraocular lens requires not only training, but practical experience.

            I have no reason to doubt that the Sponsor will provide significant training in this regard, and I have equally no doubt that this panel will insist on adequate training and proctoring. I believe, however, it is in the best interest of the patient to be informed of the experience of the prospective surgeon.

            Our organization provides a list of 50 Tough Questions For Your Doctor for patients to use as a guide in selecting a refractive surgeon. In our 50 Tough Questions we recommend that a patient seek a doctor who has performed at least 100 refractive procedures of the exact type intend to use on the patient, with the same equipment, and the same refractive error, and significantly more practical experience with similar surgical techniques.

            While this panel may find our recommendation of 100 a bit conservative and even restrictive, it does seem reasonable to assume the patient would like to know if he or she is the doctor's first unsupervised phakic intraocular lens patient.

            I respectfully request that this panel include in the patient labeling a statement indicating that training and practical experience of the surgeon may be an important factor in the probability of a desirable outcome.

            Induced Intraocular Pressure.  This panel is much better qualified to determine the safety of the Sponsor's phakic intraocular lens than I, but it appears reasonable to assume that the patient will require periodic evaluation of intraocular pressure during use of the phakic intraocular lens. Who will pay for this care?

            Phakic intraocular lens for the convenience of a reduced need for corrective lenses is an elective, arguably cosmetic, procedure. The patient who is making the decision to proceed is making this decision partly based upon cost.

            If significantly elevated long‑term care were required to maintain good ocular health after phakic intraocular lens implantation, the probable costs for examinations, visual fields, and medication to manage a surgery‑induced chronic condition would most probably be an important factor in the patient's decision to elect to have surgery in the first place.

            I doubt that it is within the power of this panel to require a doctor to provide long‑term cost estimates preoperatively, but it does seem reasonable that the patient labeling include an indication of the type and frequency of reasonably probable surgery related long‑term care.

            I'm sure that when presented with this probable treatment plan, the patient will not need the labeling to recognize that these costs should be a part of the decision regarding the relative value of a reduced need for corrective lenses.

            Endothelium.  There seems to be a lack of clear consensus on the long‑term effects of phakic intraocular lens on the quantity and quality of endothelium cells. In the clinical trials, a mandatory evaluation regime underlies the importance of this consideration. The Sponsor is requesting approval for implantation in patients as young as their twenties.         Assuming that the phakic intraocular lens would be utilized until natural cataract development when a person is in his or her sixties, the functional life of a phakic intraocular lens may be as much as 40 years. During this time, the need for regular evaluation of endothelial cell loss seems obvious.       Again, who is going to pay for these costs?

Like long‑term care for induced intraocular pressure, it seems reasonable that the patient labeling include some indication of the type and frequency of reasonably probable surgery related long‑term care.

            Summary.  The issues I raise all relate directly to the communication between doctor and patient. All suggestions are for the purpose of promoting that communication.  If properly informed of the immediate and long‑term issues relating to the Sponsor's phakic intraocular lens, I believe that those patients who elect to have phakic intraocular lens implants will have reasonable expectations and will be able to make the decision that best

meets their needs and desires.

            Lastly, I do hope that during the course of discussions today I will not hear the term "implantable contact lens". If this is a contact lens, then I've been wearing explantable phakic intraocular

lenses when I water ski.  Thank you very much for your time.

            DR. WEISS:  Thank you.  I have been told that there is someone in the audience who wanted to also participate in the open public hearing.

            DR. JOHN:  Yes.

            DR. WEISS:  Okay.  You have, well, Dr. Grimmett said eight minutes but actually it's now down to seven.  If you could identify yourself and any potential conflict.

            DR. JOHN:  Yes, ma'am.  Hi.  I'm Maurice John.  I'm an ophthalmologist from Louisville, Kentucky/Jeffersonville, Indiana, all in the same metropolitan area.  I'm medical monitor for Ophtec.  I am not paid by them at all except they paid for my plane fare and my hotel today.

            I have no stock which is very good news for Ophtec in that I don't have stock in their company.  They would be in trouble.  I implanted intraocular lenses starting in 1975.  I did radial keratotomy in 1980.  In 1993 I had a laser in Sao Paolo, Brazil and we believe the first LASIK was performed with my laser by a colleague of mine in 1993.  In 1995 I started doing LASIK in Sao Paolo to get ready for the United States.

            In October of 97 I was fortunate enough to implant the first five ARTISAN lenses in the United States.  Prior to that I had gone to Brazil and that summer of '97 implanted a couple of lenses down there.  Now I've done 200 plus ARTISAN lenses, the majority of which have been myopic and about 10 percent hyperopic.

            Starting out in October '97 I found out that there certainly is a learning curve to implanting this lens which has already been mentioned.  It is a short but steep learning curve and there is an advantage to being a good surgeon. 

            Mr. Hagele's excellent presentation mentioned that he encourages his patients to ask for a surgeon who has done 100 or more cases and that's going to be very, very difficult with an ARTISAN lens because there just aren't many of those people out on the planet.  I have a large, busy, refractive surgery practice and I don't know what that number should be but I've been doing it six years and, like I say, I've just done 200 plus of those.

            This lens needs space to be put in the eye, there's no doubt about that, but there is adequate technology to make those measurements to determine if there is adequate space.  I would also like to comment on glare.  Having done radial keratotomy since 1980 I can assure you that all those patients had starburst and glare and that did not kill radial keratotomy.

            Then I've done between five and 10 patients who are in the subset of people who have larger than 6 mm pupils and none of them have glare.  I strongly think the reason for that, especially in this population of people who are between -10 and -20 primarily they've had glare, super glare, all their life.  So if they get glare from this, it's pretty much peanut glare and then if it's a killer, then this lens can be removed really quite easily.

            After that point the problems are primarily if you estimate the anterior chamber depth they are surgeon related and we've seen that time and time again.  I introduced this lens in Brazil, as I said, in October of 1997 to my friend Eduardo Martinez who we think is the first guy to do LASIK in North or South America.  He was using other phakic IOLs and has switched to this and now gives paper presentations on it.

            I have been to South Africa many times.  I go to a meeting over there every two years and I introduced it in 1998 to some of my colleagues there.  They also had access to all the phakic IOLs that are available throughout the world. 

            My colleague, Jan Venter, is up in England now and he is working for a consortium and he gets referred all of the anterior segment surgeries that these LASIK boutiques find.  In September of last year he implanted 100 of these lenses.  That's how much he believes in their efficacy.

            The nice thing about this lens, having done a lot of refractive surgery, when I'm in the office and seeing patients, I walk by and I pull the chart off, I look at it and I see it's an ARTISAN patient  and I am so happy because I know that I'm going to be in and out of there quickly and that these patients are going to see well and we have not beat up their cornea trying to do -10.0 or 12.0 diopters on them.

            If they see 20/30 they are far happier than a 20/25 LASIK patient.  It's amazing.  My LASIK patients are always whining.  They have some slippage, especially the -7.0, -8.0, -9.0, -10.0 and they are always wanting enhancements even though they are 20/25.  These ARTISAN patients have tremendous quality of vision. 

            It's amazing to me.  I just keep reminding myself you're taking the very worse people on the plant, the one or two percent, bottom or top percent, depending on how you want to look at it, and basically pretty much nailing them, knocking a homerun every time up to the plate.

            My feeling is that patients should run to this lens and I've had some patients who you say FDA study and you've got to wait three months between eyes and they've gone elsewhere.  I've seen a couple of them come back and they said, "I should have listened.  I should have come."

            The problem we have is, and I had this in 1996, people wanted tried and true RK.  They didn't want LASIK.  We had the same thing here where 98 percent of these people's friends had LASIK, you know, quick, fast, next day, the American way, and this is a bit of a journey.  There are some people who have not had it and it's so unfortunate.  I think this lens is wonderful and thank you very much.  I hope I beat my seven minutes.

            DR. WEISS:  By 60 seconds.  Thank you.

            We will now close the open public hearing and we are going to move on to the open committee session starting with the division update.  Dr. Rosenthal.

            DR. ROSENTHAL:  Thank you, Dr. Weiss.  First, let me say that I very much appreciate Donna Lochner coming today because she is theoretically no longer with our division.  She has taken a detail with the Division of Cardiovascular Devices as their Deputy Director but has come back to deal with this lens today.  We want to wish her all the best of luck on her detail and thank her again for all the hard work she's done for our division and I know she will do a lot of hard work for the Division of Cardiovascular Devices.

            Secondly, just as a reminder to all companies, and I'll say this tomorrow as well, but it is important that all companies who are dealing with PMAs with our division schedule a pre-PMA meeting to discuss accountability, stability, safety and efficacy even if they have submitted numerous previous PMAs or PMA supplements.  This will help ensure better submission and one that will be less likely to result in a nonfiling decision or result in significant measure deficiencies. 

            I make these comments because the MDUFMA goals will have to be met in 2005 and the quality of this submission will help us considerably should it be excellent to meet our review goals.  Thank you.

            DR. WEISS:  Thank you.  we will now have branch updates by Donna Lochner and Everette Beers.

            MS. LOCHNER:  Thank you.  I am pleased to announce to the panel that Morcher's PMA P010059 was approved by FDA on October 23, 2003.  This PMA was for the endocapsular tension ring which is used for capsular bag stabilization in patients with pseudoexfoliation syndrome or other situations of compromised zonules.  You may recall that this PMA was reviewed by the panel in January of 2002.

            I'm also pleased to announce that Eyeonics' PMA, formerly C&C Vision, P030002 was approved by FDA on November 14, 2003.  This PMA was reviewed by the panel in May of 2003.  The PMA was for the CrystaLens Accommodating IOL which is intended for primary implantation in the capsular bag for the visual correction of aphakia in adult patients in whom a cataractous lens has been removed and is intended to provide near, intermediate, and distance vision without spectacles.  The CrystaLens provides approximately 1 diopter of monocular accommodation.

            Thank you.  That concludes my announcements.

            DR. WEISS:  Thanks, Donna.

            DR. BEERS:  I'm Everette Beers, Chief of the Diagnostic and Surgical Devices Branch.  Since our last update in May of 2003 we have approved three PMAs, P020050 for the WaveLight Allegretto Laser for Myopia and Astigmatism, Ms. Jan Callaway, team leader.  The approved indication was for a LASIK correction of myopia up to -12 diopters with or without astigmatism up to -6 diopters.

            We also approved P030008 which, again, was a Wavelight Allegretto laser for Hyperopia and Astigmatism.  Let me back up.  The WaveLight Myopia was approved October 7, 2003.  This one for WaveLight Allegretto for Hyperopia was approved October 10, 2003. 

            Again, Ms. Jan Callaway was the team leader.

The approved indication for this WaveLight Allegretto Laser was for LASIK correction of Hyperopia up to +6.00 diopters sphere with up to +5 diopters of cylinder with MRSE up to +6 diopters.

            On October 10, 2003, we approved P990027/S6 for the Bausch & Lomb Zyoptix, Ms. Daryl Kaufman team leader.  The approved indication here was for Wavefront-guided LASIK correction of myopia up to -7 diopters with up to -3 diopters of astigmatism and with MRSE of up to -7.5 diopters.

            We've had no staff changes since the last update in October.  During 2003 we cleared approximately 36 510(k)s.  This concludes my update.

            DR. WEISS:  Thank you very much, Everette.  That will conclude the branch updates.  I just wanted to say for the panel, Donna, that we've all valued all the hard work and the great work you've done and we're going to miss you.  Good luck in your new position.

            I will now ask the sponsor to come to the podium for presentation of PMA P030028.  There will be one hour for the presentation.  Each presenter should speak into the mike, identify yourself and your relationship with the sponsor and any potential conflicts.

            MR. McCARLEY:  Good morning.  I'm Rick McCarley, the President and CEO of OPHTEC USA which is based on Boca Raton, Florida.  OPHTEC USA is a wholly owned subsidiary of OPHTEC BV based on Groningen, the Netherlands.  We are the sponsor of the PMA under review today for the ARTISAN Myopia Lens.

            First, I would like to thank the panel for their time in preparing for today's meeting, especially the primary reviewers for their indepth review and comments.  I would also like to thank the FDA team of Dr. Lepri, Dr. Toy, Dr. Gray, and Dr. Lu for their extraordinary effort during the last six months bringing this PMA to panel.

            Finally, I would like to thank the audience for their interest and presence at today's meeting to observe the review of the ARTISAN lens.  Today's presentation will be made by Dr. Vance Thompson, an ophthalmologist from Sioux Falls, South Dakota, and Dr. Doyle Stulting, Professor of Ophthalmology at Emory University, Atlanta, Georgia.

            Dr. Thompson is an investigator in the Artisan lens study but holds no financial interest in the ARTISAN lens or OPHTEC.  OPHTEC did pay for Dr. Thompson's travel expenses today.

            Dr. Stulting was an investigator in the ARTISAN study and was engaged by OPHTEC following the PMA filing as a consultant.  He and Maurice John of Jeffersonville, Indiana/Louisville, Kentucky are medical monitors for this study.

            Also today with us is Dr. Camille Budo from Belgium.  Dr. Budo is a medical monitor for the ARTISAN lens studies in Europe and is a paid consultant for OPHTEC BV.  He will be available during the day to answer questions related to the ARTISAN lens usage outside the United States.

            Finally, Dr. Stan Bentow, the statistician for the PMA, is here to assist as needed.  Dr. Bentow is the Department Manager of Biostatistics and Data Management for Advanced Medical Optics.  OPHTEC has a business relationship with Advanced Medical Optics for the worldwide distribution of the ARTISAN lens.

            With that said, I'll turn the presentation over to Dr. Thompson.

            DR. THOMPSON:  I'm Dr. Vance Thompson from Sioux Falls, South Dakota.  I do not have a financial interest in the ARTISAN lens and my expenses for being here today are being covered by OPHTEC.

            It is a sincere honor of mine to present my experience with the ARTISAN Phakic Intraocular Lens implant to the FDA Ophthalmic Devices Panel.  After completing a fellowship in refractive surgery with Dr. Dan Durrie in 1990 I entered into private practice in my home state of South Dakota. 

            I've been integrally involved in multiple FDA monitored clinical trials as a primary investigator in United States eximer, PTK, PRK, and LASIK clinical trials.  I have completed 20 FDA monitored laser and implant clinical trials at my center.

            When I was first asked to be a part of the ARTISAN trial, I actually respectfully declined.  In 1997 I had a hard time imaging that we would be putting an implant in the eye to correct refractive error.  I received a call from an international investigator that I respect who shared with me his positive experience with this implant and asked me to look into this further.

            As a result of this call, I chose to go to the Netherlands and study with the inventor of the ARTISAN lens, Professor Jan Worst, to find out more for myself about this lens.  I was impressed with it's long track record.  I hadn't been real familiar with it at that point. 

            I basically came away with the feeling that the lens itself had some unique safety features that explain its excellent performance internationally and with good surgical techniques the outcomes were outstanding. 

            I saw patients who had had the lens implanted 12 years previously, five years previously, one week post-op, one day post-op.  I had a real good experience there and I was impressed enough to then accept the invitation to be a part of the United States clinical trial.

            So I came back home and implanted my first ARTISAN lens in September of 1998.  I have 74 eyes included in the data being presented today.  I was surprised at how quickly I became comfortable implanting this lens and how quiet these eyes looked postoperatively.

            A hundred percent of my patients have bee pleased with their outcome and they have all opted to have their fellow eye performed.  With continuing enrollment I have performed a total now of 95 ARTISAN lens implants.  After having used it, I can't imagine not providing this quality option for my patients in my practice.

            This is a single piece PMMA lens for the correction of myopia.  It is elliptical in shape and 8.5 mm in length.  It comes in two optic diameters of 5.0 and 6.0 mm.  It has a slight anterior vault to create a safety zone between it and the crystalline lens. 

            The ARTISAN lens is designed for implantation into the anterior chamber of the phakic eye.  It is fixated to the mid-peripheral iris by incorporation of a portion of the anterior iris stroma into an opening in the haptic with an instrument specifically designed for this purpose.  This process of lens fixation is known as enclavation. 

            Here is a post-mortem specimen from an 86-year-old who died from an unrelated cause after implantation of an ARTISAN lens six years previously.  Note how quiet and undisrupted the posterior uveal pigment appears.

            This slit lamp photograph shows an example of the appropriate amount of Iris tissue that should be incorporated into the lens haptic for stable lens fixation.  Proper fixation requires incorporation of about 1 mm of iris tissue between the aligned arms of the haptic.  Keep this picture in mind because we are going to be showing you a photograph of an inadequately fixated lens later in this presentation.

            An advantage of this lens is the ease with which one can attach it to the iris or detect it from the iris.  It can be repositioned during surgery for optimal centration or it can be easily removed by pushing the iris tissue back through the opening in the haptic.

            The lens is available in two optic zone sizes, a 6 mm optic in powers of -5 to -15 diopters and a 5 mm optic in powers of -5 to -20 diopters.  Here is a Scheimpflug photo showing the healthy separation of the intraocular lens from the cornea and the crystalline lens.  This is an 18 diopter lens in a patient with an anterior chamber depth of 3.4 mm.

            Since the lens attaches to a relatively immobile peripheral portion of the iris, the pupil can be dilated nicely for an unimpeded view of the retina.  The lens is implants through 5.2 or 6.2 mm incision and fixated by incorporating a portion of the mid-peripheral iris into an opening in the haptics with the enclavation instrument. 

            The surgery is performed utilizing a cohesive highmolecular weight viscoelastic.  A peripheral iridotomomy or iridectomy is required to avoid pupillary block. 

            Here is an edited video of one of my patients who had an ARTISAN implant and the first step is marking the limbus for the surgical incision and then marks are placed approximately 10 mm apart to locate incision site for the enclavation instrument.  Then the initial vertical limbal incision is made and then dissected into clear cornea.

            The entry sites for the enclavation instrument are then created, first here on the right and then now on the left.  Viscoelastic is instilled with care to avoid overfilling the anterior chamber while providing protection for the corneal endothelium and also the crystalline lens.  The anterior chamber is then entered. 

            If necessary, more viscoelastic can be instilled.  The ARTISAN lens is then rinsed.  Then it's implanted with Budo forceps, forceps that help to stabilize the lens.  The lens is positioned over the pupil.  I like to start with the lens slightly inferior to the pupil since it tends to move superior during lens fixation.

            The lens is then enclavated first on the right making sure to incorporate the proper amount of iris tissue, at least 1 mm in width.  Here we can see how easy it is to incorporate additional tissue to assure adequate fixation.  More viscoelastic can be used to maintain a nice comfortable space between the lens and the endothelium.  The left haptic is then enclavated.

            At this point in time I would like to put in balance salt solution and then the wound is closed partially.  Before the last suture is tied, the remaining viscoelastic is removed from the anterior chamber.  Then the last suture tied.

            Early designs of this iris fixated lens have been implanted for 25 years with more than 400,000 lenses implanted in aphakic eyes to date.  In 1986 a second design known as the Worst-Fechner lens was introduced for implantation into phakic eyes.  However, there was concern that the increased vault of this lens might not provide sufficient clearance from the corneal endothelium.

            In 1991 the lens was refined to address these concerns.  Note the new profile.  This design known as the ARTISAN lens has been used successfully worldwide since 1991.  The aphakic iris fixated lens is used all around the world and it is also frequently used as a secondary implant particularly during penetrating keratoplasty.

            Stable fixation over time has been shown with normal long-term pupillary function and no iris atrophy.  With iris angiogram studies, in this case two months postoperatively, it's been shown that there's no vessel disruption or leakage and normal pupillary function is maintained.

            The current ARTISAN lens design has been used for 13 years with over 100,000 myopic, hyperopic, and toric lenses implanted worldwide by more than 5,000 physicians to date.  The ARTISAN lens is the most commonly implanted phakic intraocular lens in the world today.  It is the lens of choice accounting for almost two-thirds of implants in markets where multiple phakic IOLs are available.

            I'd like to now review the results of European multi-center study of 518 eyes implanted from 1991 to 1999 at nine sites with -5.0 to -20 diopters of myopia utilizing the 5 mm ARTISAN phakic IOL.  Three-year follow-up on 249 eyes has been reported in the literature by Budo and coauthors.

            Best spectacle corrected visually acuity was better than or equal to 20/40 in 93.9 percent of patients.  Uncorrected visual acuity was 20/40 or better in 76.8 percent of patients regardless of postoperative goal.  57.1 percent were within 0.5 diopters of their target refraction and 78.8 percent were within 1 diopter of their target.

            Mean endothelial density changes in a subset of 129 eyes were as follows.  After six months there was 4.8 percent cell loss; 6 months to one year, 2.4 percent; one year to two years, 1.7 percent; two years to three years 0.7 percent.  Notice the relatively low amount of cell loss and stabilization over time. 

            The results of the European multi-center study demonstrate refractive stability and good predictability.  They concluded there was a favorable risk benefit ratio and that efficacy and safety through three years was demonstrated in this study.  There are no published reports indicating long-term safety concerns with the current lens design.

            Corneal decompensation and glaucoma have not been reported.  International experience with complications and secondary surgical intervention parallels that in the U.S. clinical trials.  I have a lot of confidence in this lens design which has been in use since 1991.  My patients and I both appreciate the fact that it is removable and exchangeable.  My personal experience has been excellent. 

            I find comfort in the long-term performance demonstrated in the European study and the published literature.  The two-thirds market share for phakic IOLs means a lot to me when the majority of surgeons in the world who have their choice of which phakic IOL to implant choose the ARTISAN lens.

            I consider this a quality surgical option for high myopes and I also consider this a quality surgical option for low myopes who are not good candidates for other refractive procedures.  I am enthusiastic about the results from this lens and I look forward to its approval.  Thank you very much for your attention. 

            I would like to now turn the podium over to Dr. Doyle Stulting who will review the results of the United States clinical trial.

            DR. STULTING:  Good morning members of the Ophthalmic Devices Panel and the FDA.  I'm Doyle Stulting, Professor of Ophthalmology at Emory University.  I'm one of the medical monitors of the ARTISAN Phase III clinical study and a paid consultant to OPHTEC.  It will be my pleasure to present the results of the U.S. clinical investigation of the ARTISAN myopia lens for the correction of high myopia.

            This was an open-label, noncomparative study of patients with 4.6 to 22 diopters of myopia.  The lens was available in one diopter power increments and two physical designs.  The 5 mm optic was available in powers from -5 to -20 diopters and the 6 mm optic was available in powers from -5 to -15.  There were eight postoperative visits. 

            Note, however, that the study was initially planned to spend two years and later extended to three years.  The results were obtained from all implanted lenses by all investigators.  Specifically, investigators for this study did not receive training outside of the U.S. or experience outside of the U.S. before they began to participate in the clinical trial.

            To be included in the original study subjects had to be 21 to 50 years old with a stable manifest refraction or refractive cylinder of 2 diopters or less, an anterior chamber depth of 3.2 mm or more, and an endothelial cell density of 2,000 or more per millimeter square.  The low-light pupil size had to be 4.5 mm or less because only the 5 mm optic was available at the time of study initiation.  There can be no ocular disease or abnormality that would affect safety. 

            The FDA granted a number of protocol waivers to allow implantation in patients who did not meet all of these criteria until the original protocol was amended with expansion inclusion criteria in November of 2000. 

            These expanded inclusion criteria allowed enrollment of eyes with clinically insignificant and stable peripheral lens opacities, astigmatism of 2.5 diopters or more, anterior chamber depths of less than 3.2 mm, age over 50, pupil size greater than the size of the optic, best spectacle corrected acuity of less than 20/40, and implantation of lenses that would not completely correct the refractive error.

            Outcome measures included uncorrected visual acuity, best spectacle corrected acuity manifest in psychoplegic refraction, contrast sensitivity, intraocular pressure, endothelial cell density, and slit lamp observations.

            At the time the protocol was developed, cataract formation was not identified as a significant risk because of a six-year history of implantation internationally without cataract induction, and the position of the implant well clear of the crystalline lens.  Thus, the approved protocol required only clinical grading of cataracts rather than standardized grading of lens opacities.

            In 1997 when the study was initiated a variety of instrumentation was permitted for obtaining specular images and only one image was required for each eye at each visit.  As the available technologies and the knowledge advanced, the sponsor changed investigational procedures consistent with FDA, ANSI and ISO discussions in developing guidelines.

            This led to a recommendation from the sponsor that sites use only the Konan non-contact specular microscope and obtain three satisfactory images for analysis for each eye at each visit.

Six hundred and 84 subjects were enrolled.  There were 662 subjects in the primary study 478 of which were implanted bilaterally.  Twenty-two were implanted for compassionate use.  Enrollment is ongoing. 

            The PMA defines several groups for analysis.  For this presentation, most safety analyses were based on all implanted eyes while efficacy studies were based on first eyes.  Accountability was adequate and the study is ongoing.  Two hundred and 32 first eyes have completed three years of follow up and 357 subjects continue to be followed.

            This PMA filing is based on 386 eyes which were followed for three years.  At three years 62.4 percent of eligible eyes have completed their exams with a large portion of the remainder still to be seen.  In judging these numbers the sponsor feels that it is important to be mindful of the fact that this was originally designed and powered as a two-year study.  Subjects were recruited with this understanding and some of them elected not to return for their three-year visit.

            The number of discontinued subjects was low with only eight percent lost to follow-up.  Demographics were not unusual for refractive surgery population with a mean age of 39.6 years.  The mean preoperative spherical equivalent refractive error was significantly higher than the mean error of patients seeking refractive surgery in this country today.  It was -12.3 diopters.  The range was 4.6 to 21.9 diopters.

            As we move forward it is important to remember that many of the subjects in this study are high myopes who have no other alternatives for refractive surgery.  This population is also at increased risk for undesirable outcomes such as cataracts and retinal detachment.  The mean lens power was -12.6 diopters ranging from 5 to 20 diopters. 

            Let's look at the safety of the lens.  One hundred percent of first eyes has best spectacle corrected acuities of 20/40 or better at two and three years after surgery.  As you can see from this slide, best spectacle corrected acuity was better at one, two, and three years postoperatively than it was preoperatively. 

            At three years 49 percent of eyes gained best spectacle corrected acuity while only 6.2 percent lost best spectacle corrected acuity.  Two eyes lost two lines of best spectacle corrected acuity.  No pathology was reported in either of these eyes so the loss is believed to be due to measurement variability.

            I want to pause with this slide because it shows something that previously approved forms of refractive surgery do not, improvement in best spectacle corrected acuity after surgery.  Indeed, the fact that only two eyes in this study lost vision is a remarkable result in view of the degree of preoperative myopia and the age of the subject population.

            The incision size --

            (Whereupon, off the record from 10:14 a.m. to 10:19 a.m.)

            DR. STULTING:  -- possible dislocation.  There were 20 of these.  The majority of these procedures were performed at a single investigational site.  Most of the procedures were preventative measures taken to avoid possible dislocation.  The sponsor advocates comprehensive training of surgeons to minimize similar events after approval.

            This graph shows the number of secondary surgical events as a function of the number of implants performed by the investigators in the clinical trial.  It is clear that the majority of secondary surgical interventions occurred during the early surgical experience.

            Approximately 50 percent of the events occurred among the first 10 subjects implanted.  A disproportionate number occurred at one site and the majority was due to improper lens fixation.  These procedures include both preventable and therapeutic interventions. 

            These data show that there is a learning curve for some of the skills required for successful implantation of the ARTISAN lens.  Retinal detachment occurred in six eyes during the observation period.  This represents an incidence of 0.3 percent per eye per year in a population of eyes with myopia between 11.5 and 18.6 diopters.  This rate is comparable to reported rates of retinal detachments in the literature in high myopes.

            This slide shows the incidence of lens opacities in the study.  Most were not visually significant or lens related.  Only one eye lost two lines of vision to 20/30.  Most lens opacities were nuclear which would not be expected to be related to an implanted lens.  Only a very few were anterior or subcapsular opacities which would be expected if they were intraocular lens related trauma to the crystalline lens.

            This slide summarizes significant lens opacities requiring cataract extraction during the study.  One occurred after removal of viscoelastic and intraocular lens implant for high intraocular pressure.

            A second was in a 50-year-old with a family history of cataracts.  The third was in a 56-year-old man with a preoperative lens opacity and a family history of cataracts.  The sponsor does not believe that the incidence of cataract in the study population is unexpected given the age and refractive error of the study cohort.

            These are the visual outcomes in eyes that underwent secondary surgical intervention.  Even in this group more eyes gained best spectacle corrected acuity than lost best spectacle corrected acuity compared to the preoperative value.  The 3.7 percent represents two eyes that lost two or more lines of best spectacle corrected acuity.

            Here are the details pertaining to these two eyes.  One was due to a retinal detachment and a subsequent macular hole 20/70.  The other was due to posterior capsule or haze following cataract extraction and intraocular lens implantation.  After YAG capsulotomy this eye had a best corrected acuity of 20/30.

            The Agency requested data on adverse events that have occurred since submission of the PMA.  There were two of these.  One was a cataract extraction that was necessitated by repair of a retinal detachment with trauma to the crystalline lens.

            The second was reattachment of a lens that was dislocated during a boxing match.  I'm not sure whether he won or lost.  The most recent visual acuities in these two eyes were 20/30 and 20/40.  Let us discuss endothelial cell density in greater detail.  At the time of initiation of the study in 1977 the protocol allowed a variety of instrumentation and required acquisition of only one image per eye per visit.

            As technology improved, the protocol was changed.  However, it was impossible to acquire old data according to the improved protocol retrospectively.  The data presented to the FDA are consistent with the guidance provided to industry by the Agency and the Ophthalmic Devices Panel at the time the study was designed.

            This slide shows the results of endothelial cell counts in the original PMA.  Although there was not significant reduction in endothelial cell density, the standard deviations of the measurements were relatively large ranging from 17 to 25 percent.

            The data set that was reported in the original PMA was derived from one to three images per eye per visit using a variety of instrumentation.  The images were analyzed by various site personnel.  Because of the variability there was not good statistical power to rule out significant changes in endothelial cell density.

            Review of the raw data led to the conclusion that analysis of the specular images could be improved.  The sponsor elected to recount available high quality images after consulting with FDA and experts in the field.  Data from 12 sites were chosen because they used the Konan specular microscopes.  This instrument is now the accepted standard for the most accurate determination of endothelial cell density.

            One reading center was employed for consistency.  Only the best quality image was analyzed per eye per visit.  There were a total of 353 eyes of 215 subjects producing a consistent cohort of 57 subjects with data at all time points throughout three years.  The average number of cells analyzed per image was 109.

            Here we see the mean endothelial cell density in all recounted subjects and the consistent cohort.  Both showed a slight reduction which would be expected even in the absence of intraocular lens implantation.

            The equivalent yearly rate of cell loss ranged from 0.72 percent to 1.59 percent throughout the study when all recounted eyes were analyzed.  Note the reduction in the standard deviations in the recount analysis.

            In the consistent cohort yearly endothelial cell density loss rates range from 0.71 percent to 1.27 percent.  This slide shows percent change for each observation period.  Changes between consecutive periods are not statistically different.  Similar results were obtained in the consistent cohort. 

            One site exhibited an endothelial cell loss for the two to three-year period of 4.95 percent which was significantly lower than any of the other sites.  The sponsor was recently notified that the site had staffing changes, problems with calibration of the specular microscope, and that the microscope required servicing during this period.  The results from this site may not be poolable.

            Removing this site from the analysis decreases the loss for the two to three-year period from 2.37 to 1.68 percent.  The accuracy and precision of specular microscopy with the Konan noncontact specular microscope is documented in the publication by Nichols and coworkers in which 25 normal subjects were examined on two occasions by two examiners.  The mean instrument error was 1.7 percent with a confidence interval from -13 to +16 percent. 

            The important point to be learned from this published paper is that a cell loss reading of 10 percent is within the confidence interval of measurement error and 13 percent of eyes would be expected to have a 10 percent change or more even if no real change existed.

            Here we see the yearly change in endothelial cell density and the two to three-year periodic rate.  These are not significantly different from guidance.  The average cell loss over time was about 50 cells per millimeter square per year or 1.72 percent per year.  The projected mean cell count is about 1,300 30 years after implantation.

            There was no change in the percent of hexagonal cells and the coefficient of variation after surgery.  These data support the conclusion that the implanted lens does not stress the endothelium because a reduction in hexagonality and an increase in coefficient of variation are hallmarks of chronic endothelial stress such as we see with long-term contact lens wearers.

            When the endothelial cell density was analyzed, there was no consistent statistically significant association with gender, age, lens model, anterior chamber depth, or preoperative spherical equivalent manifest refraction.

            We conclude that the endothelial cell density loss after implantation of the ARTISAN lens is within the acceptable range.  There are no statistically significant differences in loss rates between consecutive periods.  The loss that was recorded is within measurement error.

            In summary, the ARTISAN lens has a superb safety profile with excellent best corrected acuity.  Most secondary surgical procedures were due to inadequate lens fixation and could be prevented in the future by surgeon training and proper attention to surgical techniques.

            Even when secondary surgical intervention was necessary, best spectacle corrected acuity was maintained.  Lens opacities were generally mild, not visually significant, and unrelated to the intraocular lens.  The endothelial cell loss was within the acceptable range.

            Let's take a look at efficacy.  Ninety-two percent of first eyes targeted for emmetropia with preoperative best spectacle corrected acuities of 20/20 had 20/40 or better visual acuities at three years postoperatively.  Fifty percent of these eyes had 20/20 or better visual acuity postoperatively.

            This slide gives the details of eyes with uncorrected acuities less than 20/40 at three years after surgery.  Most or attributable to residual refractive error, usually residual astigmatism.  The sponsor believes that the reported uncorrected acuity of 20/70 in one subject was due to a testing or reported error since this subject had a best spectacle corrected acuity of 20/20 and a minimal refractive error.

            Remember that only one diopter lens power increments were available in the study.  Subjects were included with more than 2.5 diopters of astigmatism without astigmatic correction.  We expect uncorrected acuity to increase after approval because of the availability of half diopter power increments and the use of astigmatic corrective procedures when necessary.

            As we improve refractive surgical techniques, the comparison of best postoperative uncorrected acuity to preoperative best spectacle corrected acuity is becoming a more discriminating outcome measure.  In this study a remarkable 51 percent of eyes targeted for emmetropia had a postoperative uncorrected acuity better than or equal to the preoperative best spectacle corrected acuity.

            71.7 percent of eyes were within a half a diopter the target refraction and 94.7 percent were within one diopter of target.  Postoperative refractions were remarkable stable with less than a 10th of a diopter change between six months and one year and between two and three years.

            The vast majority of subjects were pleased with the quality of their vision, satisfied with their outcomes, and would recommend the procedure to their friends.  Visual aberration such as glare, starbursts, and halos were noted in about the same number of subjects after surgery as before surgery.

            The majority of subjects had no change in their reported visual symptoms after surgery compared to preoperatively.  The only reported symptom that was more frequent postoperatively than preoperatively was halos.  We may see the reason for that in subsequent slides.

            We look for correlation between visual symptoms and parameters relating to the lens or the eyes in this study.  There was no significant correlation of visual symptoms with the relationship between the lens optic and mesopic pupil size, lens power or refractive cylinder except for halos in refractive cylinder which is probably an explanation for the increase in halos postoperatively.

            After approval the sponsor believes that postoperative symptoms due to residual refractive error will be reduced because of the availability of half-diopter lens power increments and the use of additional surgical procedures to treat residual astigmatism.

            A 20 diopter myope with a 2.5 diopter corneal astigmatism preoperatively who has 20/40 uncorrected acuity after implantation and residual nighttime glare may be ecstatic about his or her surgical result but raise concern among panel members because of the presence of nondebilitating visual symptoms at night postoperatively.

            Contrast sensitivity was investigated in a substudy involving 31 subjects.  Under photopic conditions without glare, contrast sensitivity was better postoperatively than preoperatively.  There were similar results with glare reaching statistical significance at four out of five of the measured points, again with better performance after surgery than before.

            Under mesopic conditions without glare contrast sensitivity was the same postoperatively as it was preoperatively.  The same results are seen under mesopic conditions with glare. 

            In conclusion, there was no decrease in contrast sensitivity after implantation of the phakic ARTISAN lens.  Statistically significant differences where present usually show better contrast sensitivity postoperatively than preoperatively, very different than currently approved refractive surgical procedures.

            In summary, the ARTISAN lens offers excellent uncorrected visual acuity, excellent predictability, good stability of refraction, contrast sensitivity that is unchanged or improved, and high subjective satisfaction rates.  The sponsor proposes that the ARTISAN lens be labeled for the correction of myopia with lenses from between five and 20 diopters.            Although preoperative refractive cylinder greater than 2.5 diopters was an exclusion criterion for the study, the sponsor does not believe that it should be a contraindication for the use of the ARTISAN lens after approval because residual astigmatism can be managed by the placement of the surgical incision site and other techniques.

            We suggest that the lens optic size be greater than the mesopic pupil size when possible.  However, we note that no correlation was found between the disparity between optic size and pupil size and visual symptoms at night.  Because subjects in the study with preoperative pathologies did not have different results than those without pathology, the sponsor proposes that preoperative pathologies not necessarily preclude the use of the ARTISAN lens.

            Endothelial cell density minimums for each age group would be acceptable as a precautionary measure at the discretion of the panel and the FDA.  Our experience with inadequate iris fixation primarily at one site emphasizes the need for appropriate physician training in the use of this lens.

            The sponsor proposes that the lens be made available only to surgeons who have undergone appropriate training including didactic instruction, supervised wet lab training, observation of live surgery, and supervised initial procedures.

            There are a number of benefits of the ARTISAN lens compared to other refractive surgical techniques.  The ARTISAN provides excellent refractive outcomes.  As opposed to other commonly used refractive surgical techniques, the ARTISAN lens leaves contrast sensitivity unchanged or improved.

            There is a good safety profile with few complications most of which can be avoided by adequate training and surgical technique and attention to detail during the surgical procedure.  Endothelial cell loss was within the expected range and there was very high patient satisfaction.

            The lens is exchangeable and removable with good outcomes.  It avoids the potential complications of corneal surgery such as scarring, complications of flap preparation, and irregular astigmatism.  It provides an effective treatment for myopes, especially those who are not candidates for other refractive procedures.

            The sponsor asks that the ARTISAN phakic IOL be recommended for approval.  Thank you.

            DR. WEISS:  Seeing that concludes the sponsor's presentation, I would like to thank the sponsor for the clear presentation and we are going to break for 10 minutes.  I would request that everyone be back here promptly in 10-minutes time.

            (Whereupon, at 10:40 a.m. off the record until 10:56 a.m.)

            DR. WEISS:  We are going to begin with questions from the panel to the sponsor so I will ask the sponsor if they could take a seat up front.  Okay.  I'm going to be changing the format a little bit for the edification of the panel today and what I'm going to be doing is going around the table and asking you what questions you might have for sponsor in the attempt to maximize our time.

            I have one question.  You mentioned that there were three cases where the pupil size was larger than the optic size.  Did those patients have any halo or glare or visual symptoms associated with that?

            MR. McCARLEY:  Yes, they did and, in fact, there were three patients who had their lenses removed that had the optic size larger than the pupil -- sorry,, the pupil larger than the optic size.  But there were many more patients in the study that had larger pupils than the optic.

            DR. WEISS:  I think I'm confused then.  I heard from Dr. Stulting that he identified particularly three patients that had pupil size larger than optic.  But from what I'm hearing right now, there were more than three patients?

            MR. McCARLEY:  That's correct.  There were three patients.  The slide identifies three patients who had lens removal or secondary surgical procedures as a result of that.

            DR. WEISS:  Okay.  So then there were three patients with lens removal because the pupil size was larger than the optic size and they were symptomatic.

            MR. McCARLEY:  That's correct.

            DR. WEISS:  But how many patients had pupil size larger than optic size?

            MR. McCARLEY:  I'll have to pull the PMA.

            DR. WEISS:  So you can get that?

            MR. McCARLEY:  Yes, we can get that.

            DR. WEISS:  The other question on that, because of glare symptoms at night in relation to one of the people who gave a comment at the open public hearing, were any of the patients needed to be on Alphagan at night?

            MR. McCARLEY:  Not that we're of specifically for that purpose, no.

            DR. WEISS:  Okay.  So we're going to go around.  Glenda, did you have any comments or questions?

            MS. SUCH:  Two questions small in nature.  One is what was the youngest age you actually had in the study group?

            MR. McCARLEY:  It was 21, I believe.

            MS. SUCH:  That's what I thought I heard.  I can't remember the second question so I guess that's it.

            DR. WEISS:  Well, we can get back to you.

            Mr. Balo.

            MR. BALO:  I don't have any questions.

            DR. WEISS:  Dr. Schein.

            DR. SCHEIN:  I have comments coming up later but only one question now.  I'm wondering about data from other sources that could be brought to bear?

            MS. THORNTON:  Oliver would you --

            DR. SCHEIN:  My mike is too far away.  I'm interested in data from other sources on the device that might be useful.  What I've heard so far relates to this long-term series of 19 patients in Europe.  It's a consistent cohort but it's a very, very small group. 

            Dr. Stulting mentioned a publication out of Europe recently but that group reported only 50 percent of the patients that they started with.  Are there any data sources available with 100, 200, 300 patients with three, four, five-year follow-up that we can examine?

            MR. McCARLEY:  Not that we are aware of.  Obviously there have been recent publications that have started to come out where more people became involved, especially in Europe in the mid-'90s who have longer term data now.

            Dr. Mihai Pop from Canada also has some data that I believe will be produced in the next month or two in one of the major journals.  But as far as answering your question, I don't think anyone has done a large study of endothelial cell count for a long term.

            DR. SCHEIN:  I needn't even be restricted to endothelial cell count.  Something would disconnect if there are 100,000 implants that have been done and there is essentially no data externally with high levels of follow-up.

            DR. STULTING:  This is Doyle Stulting.  I can address that a little bit.  The European study was 518 eyes with a three-year follow-up on 249 eyes.  That's Dr. Budo's paper.  I think the number that you were referring to is the endothelial cell density study and that was 129 eyes followed for three years.         There probably aren't any rigorously followed series of eyes out there in the literature giving us two or three-year follow-up with the accountability that we would like to see because of the nature of the refractive surgery population.  What we do know is the number of implants that have been used and the lack of reports of significant long-term complications so that gives me at least a little bit of comfort knowing that there are so many lenses out there in eyes and, yet, there aren't reports of problems with these lenses long term.

            DR. SCHEIN:  In Europe is there mandatory reporting with explantation?

            MR. McCARLEY:  Yes.  In fact, it's required as part of the CE process.  In Europe they do require you to report adverse events -- all adverse events.

            DR. ROSENTHAL:  May I just add that as part of the PMA process it's the sponsor's obligation to submit all data that's been published that they know of in the literature and not in the literature about the device.  The FDA does receive everything that is supposed to be -- that is out there.  It's supposed to be submitted with the application.

            DR. WEISS:  Dr. Macsai has a question on that point.

            DR. MACSAI:  I have a question for Dr. Rosenthal.  Does that include CE data?  Do you share with CE and does CE share with the FDA?

            DR. ROSENTHAL:  The data we are supposed to receive is the data that the company submits that they know is in the public domain.  CE data may not be in the public domain.  Many of the countries within the European community consider much of the adverse event data to be confidential. 

            I think with Britain we do have some sort of mutual agreement that when there are serious problems with the device, we are notified and, likewise, they are notified when we have serious problems.  But generally there is not a worldwide sharing of data relating to post-market problems with devices.

            DR. WEISS:  We're going to go on to Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  Thank you.  I just have a couple of questions about the endothelial cell count data that was presented in the PMA.  The first is that there were 12 sites that contributed data to the final analysis.  I'm wondering if you can tell us whether you've analyzed data to determine how those sites compared to the sites that did not contribute data to that analysis other than not having the Konan microscope, things like case mix, provider experience, anything like that?

            MR. McCARLEY:  The Konan machine provides a relatively good image that is standard.  And they also provide a separate software that actually provides a way to read images in the standardized way.  It was out choice based upon the recommendations of the experts, some of which have testified in front of this panel, which machine is likely to give you consistent good readings.  Not favorable readings but to be able to read it at all.  In fact, we utilized exactly the same machines as Dr. Edelhauser, for instance, and some of the others around the country that actually do endothelial cell counts.

            DR. BANDEEN-ROCHE:  But what I'm getting at is that only 10 of the U.S. sites use that microscope and how might those sites have been different than the others?

            DR. STULTING:  Maybe I could ask Dr. Bentow for a little bit of help.  Did you look at the baseline for the two sites?

            DR. WEISS:  You can identify yourself.

            DR. STULTING:  For the groups of sites that were included in the endothelial cell versus those that were not.

            DR. BENTOW:  Yes, this is Stan Bentow with AMO.  We didn't look at a comparison with the previous data set because we went with only the Konan pictures that we used in the latter one, although we did look at site comparison and analysis for that data set, the recounted data set.

            DR. SCHEIN:  Did you make a comparison --

            DR. WEISS:  Dr. Schein, can you identify yourself?

            DR. SCHEIN:  Right.  This is Oliver Schein.  Did you make comparisons within those centers that were using the Konan scope as to who is in versus who is out?  By that, I mean you have images on a very small proportion of the total images that were generated even at the sites that used that technology.  It would be useful to know rates of adverse events in versus out, baseline cell counts, age, etc.  Do you have those to show us?

            DR. BENTOW:  We can look at that and see if we can bring that up.

            DR. WEISS:  Thank you.  Dr. Bandeen-Roche, if you have no other questions.

            DR. BANDEEN-ROCHE:  I have one more question that actually goes to that.  I believe I read in the updated part of the PMA that images with the number of cells counted less than 70 per reevaluated and if it was felt that they weren't of good quality, they were not eliminated.  This seems potentially biasing to me.  It seems like that could well undercut the rate of loss by excluding the images with the low cell counts.  I wanted to give you a chance to respond in case I'm just not understanding.

            DR. STULTING:  I understand what you're asking.  I can tell you that the site that we mentioned that had the high rate of secondary surgical procedures and what not was one of the sites that was included in the recount data.

            DR. WEISS:  Dr. McMahon.

            DR. McMAHON:  Tim McMahon.  I have two questions.  The first continues along the line of endothelial cell counts.  Were test and retest analysis done by individual sites and were there any variances in the 95 percent confidence intervals amongst those sites?

            DR. STULTING:  No, looking at test/retest for a single site was not part of the protocol.  Once again, the protocol was developed back in 1997 when these kinds of questions were really not at the top of our minds and we weren't looking for a technology that gave us the ability to discriminate a .6 percent loss from a 1.6 percent loss over a period of a year.  Those parts of protocol that we might want to design today for a very scientifically rigid investigation were not part of the investigation that we are reporting today.

            DR. WEISS:  We do not have the amount of time to have the sponsor coming up to the podium at this point so we are going to have to continue along with these questions.

            Dr. Bradley.  Oh, I'm sorry.  Dr. McMahon.

            DR. McMAHON:  This is my second question and it's in a completely different area.  I was troubled by the number and percentage of protocol deviations.  I think it was as high as over 20 percent and I'm kind of concerned as to what the rationale for that was.  There are a couple of cases identified. 

            In particular, initially three comments or comments about three patients with pupils larger than the optic and now new statements saying that there's more than that.  There's protocol instructions and inclusion/exclusion that prohibits that and what is the justification for all these?

            DR. STULTING:  We tried to address this question in the presentation since it was raised in some of the comments from the panel that were forwarded to the sponsor.  The original protocol that was designed in 1997 had exclusion and inclusion criteria. 

            For example, for astigmatic error that was present before surgery patients who were high myopes who had no other choice of refractive procedures requested ARTISAN implantation.  Their surgeons requested it from the sponsor.  The sponsor requested  protocol deviations for the FDA for use compassionately in these patients and it was granted.

            As the time went by eventually in the year of 2000 the FDA and the sponsor expanded the protocol inclusion criteria so that patients with anterior chamber depths less than 3.2 mm, pupil sizes greater than the optic size and high astigmatism could be implanted with informed consent and so these patients were later included in the protocol and that's how they got in there. 

            It wasn't because investigators enroll people that they shouldn't enroll.  It was because the indications were expanded with informed consent, knowledge of the Agency, and a decision on the part of the sponsor.

            DR. McMAHON:  So the FDA okayed each one of these?

            MR. McCARLEY:  This is Rick McCarley.  Initially we received very few requests for protocol deviations in our study.  As time progressed and we believe as surgeons became more comfortable with the procedure, the surgical technique itself, they started to receive more patients and see more patients that they believe could be assisted by it but, in fact, at the same would not be compromised. 

            We started to get more and more requests for protocol deviations.  We worked with the FDA, the Agency, to create an arm, a substudy.  It's called Protocol Deviation Substudy.  All of the criteria except a certain list of items that Dr. Stulting mentioned were included.  These patients signed an additional informed consent on top of the normal informed consent for the study.

            DR. WEISS:  I would just follow through and I'm just repeating what you said.  What percentage of the protocol deviations were granted with the update approval and what percent were not?

            MR. McCARLEY:  All of them were --

            DR. WEISS:  A hundred percent.

            MR. McCARLEY:  A hundred percent were known by the FDA or approved by the FDA.  We either gained approval from the FDA on a one-by-one basis before the substudy started and after the substudy started they were approved by the institutional review boards.  The patient included them in the normal enrollment.

            DR. WEISS:  So 100 percent were approved by the FDA before they had the surgery.

            MR. McCARLEY:  Correct.

            DR. WEISS:  Dr. Bradley.

            DR. BRADLEY:  The sponsor emphasized that the procedure led to improved visual acuity and improved contrasensitivity.  I wondered if the sponsor had evaluated the relative importance of image magnification and image quality on these changes in acuity in contrasensitivity?

            DR. STULTING:  We recognize image magnification and we recognize the potential improvement in image quality because of the placement of the corrective lens but nothing was designed in the protocol to look at these things specifically, objectively, and scientifically other than the collection of data that you have in front of you.

            DR. WEISS:  Dr. Macsai.

            DR. MACSAI:  I just want to first follow up on your comment, Dr. Stulting.  This increased visual acuity that was shown on the slides during your presentation is accountable due to the magnification of the IOL.  Correct?

            DR. STULTING:  Some of it is.  That's correct.

            DR. MACSAI:  And in your contrast sensitivity studies, how was the contrast sensitivity measured preoperatively as for point of comparison?  Was it measured in spectacles?

            DR. STULTING:  Yes.

            DR. MACSAI:  So what did you expect if someone is -12 in their spectacles that their contrast sensitivity would be decreased versus that with an intraocular lens?

            DR. STULTING:  Are you asking --

            DR. MACSAI:  Would you expect these results from placement of an intraocular lens?

            DR. STULTING:  I think I would and I think I would be pleased.

            DR. MACSAI:  It's because of the difference between the spectacle and the movement of the lens inside the eye and the lack of changes in refractive index.

            DR. STULTING:  That's probably correct.

            DR. MACSAI:  Okay.

            DR. WEISS:  Dr. Grimmett.

            DR. GRIMMETT:  Dr. Michael Grimmett.  My first question was already addressed by Dr. Macsai and Bradley regarding magnification.  The second point I wanted to make was that Dr. Stulting showed a slide regarding the lack of change and hexagonality and coefficient of variation.  This was a fairly young cohort of patients, I think, ranging from 21 to 50 something with an average range in the 30s, I believe.          As Dr. Edelhauser confirmed on our October meeting when I asked him the same question, a young cohort can have a very robust endothelium and really mask the morphemetric data so it's stress factors that we all think of regarding these changes which may manifest in an older subgroup can be completely hidden in populations this young.  I just wanted to point out that fact when we considered the endothelial data.  That's all I have.

            DR. WEISS:  I had one other question in terms of trauma dislocating this lens.  Would you then advise patients who were in careers such as boxing or hockey or whatever that that would be a contraindication to having the lens?  Basketball depending on how you play it?

            DR. STULTING:  I think that's a reasonable suggestion.

            DR. WEISS:  Dr. Mathers.

            DR. MATHERS:  Dr. Bill Mathers.  I seem to feel a sort of disparity between the study -- the mean of the study group and that which the sponsor is asking permission to include later.  The mean here was 39 years of age and -12 refraction.  It might be that this is actually the group that you feel that this lens is the most advantageous for and has the greatest impact. 

            In fact, one could say that Dr. Stulting's comment that there is no other choice for some of these people may be a factor but you are requesting permission for patients down to 20 and a refractive error that is much lower than this.  How do you -- help me with feeling how these two groups actually compare and the justification for using it in a larger group.

            DR. STULTING:  The profile of the refractive -- of the patient population in this study pretty much parallels the clinical practices and the refractive populations that are part of publications for refractive procedure in the literature so far.  The mean age, in fact, for all of these is pretty consistent at 39.

            As a consumer of this technology, I would like to have it available to me to use in circumstances for I feel it is appropriate.  There may be a relatively young patient who has a relatively thin cornea who would be an appropriate candidate for it based on parameters other than age. 

            I would like to have it in my armamentarium so that I can offer it to that person.  I think that the selection of procedures for refractive surgery has to be based on many more things than the refractive error and the age.

            DR. WEISS:  Dr. Casey.

            DR. CASEY:  Richard Casey.  Dr. Thompson, you showed a slide and you made the comment that there was no iris vessel disfunction or leakage in patients in this study, but the title of the slide was an angiogram two months post-op with an aphakic IOL.  My question is was there a systematic evaluation by angiogram of patients in this study?

            DR. THOMPSON:  No.  We didn't do angiography in this study.  We were basically showing that because some of the disadvantages of other implants in the past than chronic cell and inflair from vessel leakage and we wanted to show the integrity of the blood/aqueous barrier for this lens.

            DR. CASEY:  My question was related to there was a small number of minority patients in this study and we know that there are patients that have different -- the iris is of different thickness and different vascular density and so issues of inflammation could be important in different subpopulations.  If it wasn't done, it wasn't done.

            My second question is can you tell us anything about the endothelial cell loss in those patients who required a second surgical procedure and were they followed after the second procedure to determine if there was any accelerated rate of attrition of endothelial cells?

            DR. STULTING:  We can try to get those numbers specifically for you after lunch but I can reiterate the point that I made before and that is that the site that had most of the secondary surgical procedures was one of the sites that was in the recounted endothelium cohort so we have a good bit of information on those patients in particular.  Let me make a note of that and we'll try to get the data.  The specific question is endothelial cell counts on people with secondary procedures.

            DR. CASEY:  Yes.

            DR. WEISS:  Dr. Coleman.

            DR. COLEMAN:  Yes, this is Anne Coleman.  I had a question regarding your exclusion criteria for patients with glaucoma.  How is that determined for those individuals to be excluded?  Was it by visual field and optic nerve evaluation, or was that by clinical judgment?

            DR. STULTING:  I'm afraid we didn't probably use the strict criteria that a good glaucoma specialist would request.  It was based on clinical diagnosis and the use of medications.

            DR. COLEMAN:  And then --

            DR. STULTING:  A refractive surgeon's diagnosis, I guess.

            DR. COLEMAN:  And then at one, two, and three years how many of the patients were on chronic glaucoma medications for maintenance of intraocular pressure?

            DR. STULTING:  Ten out of 1,147.

            DR. COLEMAN:  Thank you.

            DR. WEISS:  Dr. Van Meter.

            DR. VAN METER:  Woody Van Meter.  A couple of questions for Dr. Stulting.  Early on in your presentation you were talking about training and mentioned that all investigators were trained for this study in the United States.  Is that correct?

            DR. STULTING:  That's correct.

            DR. VAN METER:  We had anecdotal evidence from Dr. John about multiple procedures done in South America and South Africa and those patients were not part of this study.  Dr. Grimmett has already covered my concerns about the statistical legitimacy of the endothelial data and I guess we can talk about that later.

            On slide No. 60 that you showed, there was reference to a 56-year-old with a preexisting cataract who had a family history of cataracts who had an ARTISAN lens implanted.  That seems to be a little bit outside the box.

            MR. McCARLEY:  Rich McCarley.  There were actually two patients in the study that had a family history of cataracts but that wasn't found out until after the patient had actually received the implant.  In one case I'm very familiar with, the surgeon implanted the first eye and six months later was getting ready to implant the second eye and noticed the cataract in the first eye.  Upon further interview with the patient found out, in fact, it was familial.

            DR. VAN METER:  Well, I'm not concerned about the family history as much as I am the 56-year-old who was already presbyopic and nearing cataract age anyway must have had it noticed beforehand since it was called a preexisting cataract.

            MR. McCARLEY:  It wasn't and the patient chose the surgery.  The surgeon felt that there was a possibility that it wasn't likely to develop.

            DR. VAN METER:  Okay.  Thank you. 

            Dr. Stulting, slide 80 you mentioned that proper training will reduce the incidence of complications.  Since we have data here from the finest surgeons in the world doing these cases, how are you going to alter the training technique that is listed in slide 102 to reduce complications when mere mortals try to do the surgery?

            Slide 102 lists a number of objectives from training, most of which I believe are already, as I peripherally understand it, part of the ARTISAN training program.  Can you tell me how you are going to change the training?

            DR. STULTING:  I'm not exactly sure that I understood the question.  Could you repeat it?

            DR. VAN METER:  Yes, sir.  On slide 70 you mentioned that proper training will reduce the incidence of complications.  Slide 102 you list the training proposal but, as I understand it, this training proposal is pretty much how training has existed for ARTISAN investigators.

            DR. STULTING:  I don't think -- there is no question that this surgery is different from what ophthalmologists are used to performing as you could see from the video clip.  There is bimanual dexterity that is involved.  It's a little bit greater than the bimanual dexterity that we are used to having in other procedures that we perform.  That will have to be taught.

            As a result of the clinical trials, there are techniques that we have learned that need to be taught perhaps differently, emphasized differently than were done in the clinical trial.  We think that those will be possible to teach and that, I guess what you said was, mere mortals will be able to perform those techniques. 

            After all they do in the rest of the world outside the United States using the data that we showed you from Market Scope with implantation of phakic IOLs.  This is the most common phakic IOL that is implanted outside of the United States where ordinary surgeons have a choice of intraocular lens implants to use and this is what they choose to use.

            We think that the experience that we have had has made us better at picking out skills that we need to teach and in recognizing methodologies that can be taught to improve the performance and that's what we've learned from the clinical trials. 

            We would prevent all complications from the lens?  Probably not.  We still see complications from cataract surgery and other procedures that we perform.  I don't think technique will be any different but I think that the risks are well worth the benefit.

            DR. VAN METER:  Thank you.

            DR. STULTING:  May I pass the mike off to Dr. Thompson?

            DR. THOMPSON:  Just a quick comment.  I consider myself a mere mortal and I get way more stressed out going into cataract surgery than I do going into doing ARTISAN.  I have not found the training to be difficult.  Approximately after five implants I had a nice comfort level so I do not think we are going to have a hard time getting ophthalmologists comfortable with this procedure.

            DR. WEISS:  Dr. Smith.

            DR. SMITH:  Janine Smith.  I wanted to echo Dr. Bandeen-Roche's concerns regarding any data you might have on differences in the cases of patients that had gradable specular images for the endothelial cell counts. 

            I wonder if you have any data on the proportion of eyes that have gradable specular images in the 12 sites that had the Konan microscope?  So that's one, the proportion.  The second is could you identify any difference between the cases and people that had gradable images and the ones who didn't. 

            My concern is from my experience with that particular instrument which has issues that I'm sure we'll talk about later, it happens to be the corneas that have some abnormality that it is much more difficult to get good images in so you can understand why this might be an important question.

            DR. STULTING:  I appreciate the comment and made note of it and we'll try to address it.  I can tell you from having looked personally at many of the images that were obtained during the first part of the study the problem with the images wasn't that there were very few cells, large cells, and unusual cells with Gute and other abnormalities.  The problem was focusing, properly counting and whatnot.  They were technical problems but I've made note of the question.

            DR. WEISS:  Dr. Huang.

            DR. HUANG:  I have some concerns about the safety and efficacy for this procedure in the low myope patient.  As we all know, there are many refractive surgery options for the patient with low myopia nowadays.  I'm just wondering that in the low myope patient with slightly shallow anterior chamber is the safety equity maintained and achieved in the efficacy of this procedure?  Is it just as effective or as safe as some other existing procedures?

            DR. STULTING:  That's a good question and a good consideration.  We looked at endothelial cell losses in patients who had more narrow anterior chamber than those who had deeper chambers and didn't find a correlation with that. 

            Having said that, I appreciate your concern.  The sponsor believes that this is a technology that should be made available so that it can be used at the discretion of the well-trained and discriminating refractive surgeon. 

            With the information in hand and the proper training, that surgeon can make a reasonable decision about what is the best technology to offer the patient.  It's possible that a low myope may do better with an intraocular lens implant because of his corneal anatomy. 

            Perhaps it's someone who has questionable form fruste keratoconus and the surgeon doesn't want to take a chance on getting ectasia postoperatively.  In that particular case the balance may fall toward an intraocular lens implant when for the routine patient with low myopia a corneal procedure may be most appropriate.

            DR. WEISS:  Thank you.  We have one question from Dr. Macsai and we have one from Ms. Such and we'll do those two and then we'll conclude this portion.

            Dr. Macsai.

            DR. MACSAI:  On the panel someone had asked about the endothelial cell counts in the patients that had their implant repositioned, etc.  I was wondering if you could give us the endothelial cell data on the entire Group E because I did not have that to review prior to this meeting and I would like to see the consistent cohort within Group E, the entire Group E.  I think that is incredibly important because, as Dr. Van Meter stressed, we are mere mortals and what happened in that group is important.

            DR. STULTING:  I'll add my name to the list of mere mortal ordinary surgeons.  To address your question, let me make note of that and see if we can get data for you when we come back.

            DR. WEISS:  Glenda.

            MS. SUCH:  Glenda Such here.  Aside from thanking Dr. Weiss for bringing up the concern about what activities besides boxing and basketball or whatever a consumer might want to avoid doing, I believe during one of the discussions from the presenter we heard that nighttime activities that would be affected aside from having starbursts and halos during driving, one of the presenters actually had said the word newspaper print.  I was wondering what other types of activities or type of events you've actually noticed being hindered by this lens with low illumination?

            MR. McCARLEY:  We haven't had any reports as the sponsor from a site or from a patient that they have been hindered in a nighttime activity from having glare or halos or starbursts or any other visual effect.

            MS. SUCH:  Not during driving either?

            MR. McCARLEY:  That's correct.  None that inhibit them from doing that.

            DR. WEISS:  One question in terms of the induced astigmatism, Doyle.  You had mentioned that this was most likely from the wound.  I assume corneal topographies were done to just confirm that anyone with astigmatism or maybe in some patients that, indeed, it was wound induced?

            DR. STULTING:  Corneal topography was not part of the protocol.

            DR. WEISS:  Okay.  So it was sort of more the assumption or it went along with the refraction where the astigmatism was and where the wound was placed?

            DR. STULTING:  Right.  We have refractions before and after and vector analyses to look at the astigmatic change from one to another.

            DR. WEISS:  And the astigmatic change would be consistent with the placement of the wound or did anyone -- is this just an assumption or did anyone actually look at it?

            DR. STULTING:  We didn't look at it probably in a sufficiently organized way to really address that.

            DR. WEISS:  Okay.

            DR. STULTING:  I think it was sort of believed that the investigators were sufficiently familiar with wound placement for cataract surgery that they understood what it would do.

            DR. WEISS:  Thank you.  I want to thank the sponsor and we are now going to go on to the FDA presentation.

            DR. TOY:  Good morning, panel members.  I'm Jeff Toy, the team leader for this PMA P030028, phakic IOL for the correction myopia.  The sponsor has already given an excellent introduction of the results and a description of the device so I only have two slides to add.

            This first slide is just to acknowledge the PMA review team.  They did a good job of expediting the review of this PMA.  The team members are Don Calogero, Carol Clayton, Gerry Gray, Susan Gouge, Sue Jones, Bernard Lepri, T.C. Lu, Elizabeth Riegel, and Pam Reynolds.

            Second slide is just the order of speakers for FDA presentation.  Dr. Lepri will be first and giving summary of the clinical results and posing the question to the panel, and Dr. Gray will be second with the statistical analysis of the endothelial cell count.  Thank you.

            DR. WEISS:  Thank you, Dr. Toy.

            Dr. Lepri.

            DR. LEPRI:  Good morning, members of the panel, FDA colleagues and guests.  In my presentation this morning I will just present to you some highlights that you will need for consideration for making your recommendations today. 

            This panel has specific goals to achieve today and those will be for us to assess, evaluate, and identify.  We'll be assessing the risks and benefits and evaluating the effectiveness and safety outcomes presented by the sponsor and the PMA and their presentation here today.

            Some of the risks that we've identified are operative and postoperative.  Operative risks may include improper enclavation leading to surgical repositioning, wound leakage, infection, induced cataract and/or corneal damage due to surgical trauma.

            Postoperatively one may see elevation of IOP inflammatory responses, the potential for pigmentary glaucoma as a result of iris irritation, critical losses of corneal endothelial cells and function, retinal detachment and dismemberment of the IOL itself with concomitant optical side effects such as glare and halos, etc.

            Correction of high refractive errors without the optical limitations imposed by spectacles and the complications of long-term wear contact lenses is perhaps the major benefit for the patient, while reversibility and expanded options for treatment of high-refractive errors benefit both the practitioner and the patient.

            I'm going to give you a capsule view of the effectiveness and safety outcomes that were presented here today.  Under effectiveness some major highlights are UCVA, BSCVA, predictability of RSE, and the stability of the MRSE.

            Uncorrected visual acuity of 20/20 or better was achieved by more than 30 percent of the overall treated subject population at one, two, and three years.  UCVA of 20/40 or better were achieved by greater proportions ranging from 84 percent up to 87 percent over the three-year period reported in the study.

            As one would expect, BSCVA shows that at least 79 percent have 20/20 or better and essentially 100 percent had BSCVA of 20/40 or better in the overall treated population.  The ARTISAN showed a high degree of predictability in targeting refractive correction.  At least 72 percent were within a half diopter of intended correction and 94 percent and higher were within 1 diopter.

            At present refractor procedure stability is determined by evaluating the proportion of eyes that show variability in refraction no greater than 1 diopter between consecutive visits and refractions at least three months apart and mean differences of less than .5 diopter over a yearly interval. 

            The ARTISAN study population showed 95 to 98 percent were within 1 diopter of refractive change between consecutive refractions and mean differences in refraction ranged only from -.02 to -.05. 

            Safety issues where the BSCVA, which was already discussed, induced astigmatism, cells and flare, corneal edema, increased IOP or glaucoma, cataracts, and endothelial cell loss and corneal compromise. 

            Induced astigmatism of 2 diopters or more was reported in proportions ranging from two percent to 3.5 percent and the established target for refractive procedures has been set for less than 5 percent.  The rates of inflammatory responses postoperatively were in the expected ranges that one would expect for this type of surgery. 

            While there were several reports of elevated IOP none persisted beyond 20 days post-op and were secondary to either postoperative steroid treatment or a few cases of incompletely aspirated viscoelastic.  The cases that require short-term treatment all responded adequately.

            While there were 49 lens opacities reported in the study only four were visually and clinically significant.  The others were due to careful observations on the part of the investigators identifying normal age related chances in the crystalline lens.  And of the visually significant cataracts three required extraction and the fourth one resulted in a loss of two lines of BSCVA but, to the best of my knowledge, was not worse than 20/40.

            While there were no cases of actual corneal compromise reported during the investigation, endothelial cell loss changes were reported during both the short term in the domestic study and in the scant but long-term data from the European study.  Dr. Gray will present the detailed analysis of these changes following my presentation.

            I'm going to ask you to identify thresholds of critical inclusion criteria to minimize risks and perhaps the population it may benefit most.  With considerations for the outcomes presented to you by the sponsor here today and in the PMA, the panel will be asked to make these recommendations regarding patient selection criteria, the risk benefit ratio of this device, and its associated surgical procedure and to establish criteria for product labeling if approved for marketing.

            The use of phakic IOLs for the correction of refractive errors shows concern for the long-term effects upon the integrity of the corneal endothelium.  The entry criterion established by this sponsor at the inception of this study was a minimum pre-op cell count of greater than or equal to 2,000 cells.

            On the next slide and on slide 32 I need to make a correction.  The mean pre-op starting is 2,754 and not 2,500 as on the copy of the slides that you have in front of you.

            The sponsor's response to FDA's challenge of endothelial cell change data outcomes resulted in the sponsor's development of the charts you see presented here in this slide.  Assuming a baseline cell count of 2,754 cells and assuming linear loss over time, the sponsor shows that after 30 years the cell count may drop to 1,272 cell per millimeter-squared.  Of course, it is important for us to keep in mind the large margin of error viewed by spectral microscopy and the mathematical assumption of linearity and cell changes over time in these calculations.

            The very nature of endothelial cell examination and change is affected by many variables.  One variable identified in this study was anterior chamber depth.  While the same size was low, it is particularly relevant to the ARTISAN lens its position in the anterior chamber and one can see from the six-month post-op period to three years for the seven eyes having anterior chambers ranging from 3.0 to 3.2 mm that there was an estimated cell loss of 8.99 percent.

            The ARTISAN also offers two models whose optic sizes vary.  They are 5 mm and 6 mm and relate to the patient's pupil sizes.  The relevance of these optic sizes is related to performance in low-light environments and the potential for symptoms and complaints of glare and halos that may impact functioning such as in nighttime driving.  The sponsor presented the outcomes of patient satisfaction by questionnaire responses for our consideration. 

            The implied refractive benefits of the ARTISAN have already been discussed here today and are directly related to the targeted refractive range.  You will recall that only a small percentage of eyes were treated below -8 diopters of myopia.

            I am not going to present the questions now.  We will present the actual questions to you following Dr. Gray's presentation of the endothelial cell data.  Thank you.

            DR. WEISS:  Thank you, Dr. Lepri.

            DR. GRAY:  Good morning.  My name is Gerry Gray and I'm going to discuss the results from the endothelial cell counts in this study.  I'm the team leader for the Cardiovascular and Ophthalmic Statistics Team.  This submission was mainly reviewed by a member of our team, T. C. Lu.

            Just a synopsis of what we're going to be talking about here.  The purpose of the endothelial cell count is to investigate the effects of the device on the endothelial cells through time.  We have endothelial cell counts and measurements from specular microscope photographs.  There are multiple images for eye after all 2,000.  We have counts at baseline six months one, two, and three years.

            As you've already heard in some detail from the sponsor, there was a very large variability in the initial set of data and so images were reread as possible and the net result is we have 353 available eyes from reliable machines that were recounted in one reading center.  That was a total of 1,144 actual observations eyes by visit.  As a statistician I need to point out that we don't have any control group here so it's very difficult to evaluate the results without an actual control.

            So there is no control and the question is what do we compare these results to?  We want reasonable assurance that the endothelial cell density is preserved.  The normal loss due to aging is apparently around 0.6 percent per year.  The point for concern appears to be around 1,000 to 1,200 cells per millimeter-squared.

            There are several sources of guidance or preliminary guidance and they are all written in terms of trying to place an upper confidence limit on this rate of loss.  The FDA draft guidance and the discussion from this panel several years ago set an annual rate from three months to three years, an upper 90 percent confidence limit of 1.5 percent.

            The ISO and ANSI documents are not actually, I don't think, written in terms of standards for acceptable rate of loss but those both suggest you calculate a sample size for this kind of study using a 2.0 upper 90 percent confidence interval.

            Here is a visual representation of the data that we do have from a recount study.  Each vertical bar is one of the visit, base line six months, one, two, and three years.  The green indicates that we have actually a count in that time and the white indicates we don't.

            Individual eyes can be read horizontally across here.  Here on the bottom are the 57 eyes that were measured at all time points.  There were 126 extra eyes that had a baseline measurement and by the end there is actually 50 of them left here so there's 107 eyes that have both base line and three-year measurements.

            Then there's a fairly large portion of eyes, 170 right here that have no baseline measurement.  Then you can see these numbers indicate the number of people that started in at those various points in time.

            A couple of comments on this graph.  This is not the normal pattern.  We are used to dealing with

-- this is not the normal pattern of missing we see where initially everyone has a baseline and people drop out through time. 

            This is somewhat unusual because we have this very large group that actually doesn't have measurements at the beginning.  That was, I'm pretty sure, due to the fact that the study was sort of given a lot more importance part way through.  Initially we don't have baseline measurements for these people.

            Another comment that I want to make that came from the discussion, the earlier questions, the question of is there a bias problem because perhaps some of the measurements are thrown out because they were low.  The question is how is that going to change the rate of loss through time if there's a bias?

            What I want to point out is that if there's a bias, there's more people missing here at the beginning than there are at the end so I'm not sure if there's a bias how it would affect any kind of results we have here today.  I think that's an unanswerable question.

            This is a plot of the actual data that we do have, the 1,140 observations from 353 eyes and the blue line just connects the means at each time point.  The red line across the bottom, just for your reference, is 1,200 cells per millimeter-squared.

            Now, what we're interested in is the steady state, if you want to call it that, the long-term loss that we can expect to see.  That estimate depends on a lot of things.  It depends on the model that we use, whether we account for an initial operative loss or not so the function of formal use, whether we use the baseline in the end or some form of regression, the cohort we use, the details of the statistics. 

            As an aside, it's not entirely clear to me that natural loss for untreated patients is actually steady state either.  That further complicates any kind of extrapolation you want to make.

            All that aside, there's really not that much variability in the estimates of long-term loss from these data.  The sponsor presented an annual loss of 1.7 percent based on 183 eyes but had a baseline count.  That calculation is based on a regression that includes the baseline.  A 90 percent confidence interval for that is 1.3 to 2.1 percent.

            An alternative that I think might be slightly better uses all the data that we do have and tried to account for the missing using something called multiple imputation.  That actually gives a fairly similar result, 1.8 percent annual loss, 90 percent confidence interval 1.3, 82.2 percent.  Both of these estimates account for correlation within patient in a reasonable way.

            Here are the results from the best, the 1.8 percent loss per year. If you actually pull out the other one on top of this, the lines are virtually superimposed.  It looks almost the same, 1,200 cells per millimeter still there as a reference.

            Now, of course, this is what we have so far for three years and what you really are concerned about is what happens in 10, 20, 30, or 40 years so we want to do some extrapolation if we can.  Before we do that, it's my duty to remind you that we are trying to -- it's always a questionable exercise to extrapolate and we are trying to extrapolate 10 times the range of the data that we do have.

            All that being said, though, probably some type of -- you have to make some extrapolation to make a judgment, either formally or informally.  If we do it formally, it's very dependent on the model we use and the assumptions we want to make, is it linear, exponential, whatever kind of decay. 

            The problem is with only three years of data we can't really distinguish between these models.  There's no way of telling what happens if things change in 10 years.  Because of that I think you also should really consider if it's necessary to obtain good long-term data and how you might want to go about that.

            One more thing.  We do have some additional long-term information that has been referenced previously.  The sponsor has provided additional four-year data on 27 patients who showed a 1.63 percent loss between three and four years.  Then there is some additional long-term information from a 19-patient European cohort. 

            Basically the same follow-up is in this study but there is an additional point t 10 years.  For those patients their mean counts went from 2,666 to 2,180 at 10 years.  That's an 18.1 percent decrease over the 10-year period.  Six percent of that was in the first six months. 

            That translates into annual rates that you see down here at the bottom, 1.2 overall.  The rate between six months and three years was actually fairly high, 2.9 percent, and the rate between three years and 10 years is actually fairly low, 0.7 percent.  You can make what you will of that.

            After we got all the caveats and other data aside, here is a picture of the linear extrapolation that you would produce using the 1.8 percent loss per year.  On the graph are also confidence limits, the dash lines of the confidence limits on the regression and the dotted lines are the confidence limits for predicting an individual.

            You can see there is a fair amount of variability and what really matters is right from here there is a fair amount of variability in this direction.  In other words, the variability and the time the person might take to reach 1,200 cells per millimeter-squared.  All this, of course, still assumes that whatever happened in the first three years is going to continue linearly for the next 37.

            Using a linear model we can actually -- and using the rates of loss that we get based on the estimates we produce we can produce a table that shows the years until predicted 1,200 cells per millimeter-squared.  You can see of you start out at 2,000 cells then after 12 to 17 years, depending on how cautious you want to be. you are going to be at around 1,200.               If you start out with 3,200 cells, then you have maybe 30 or 40 years until you reach 1,200.  Again, this all should be taken with a grain of salt because it's an extrapolation and there is a fair amount of error.

            Maybe a little more important than the average cell loss through time is a question of how are the individual patients faring here.  In other words, what proportion of the patients are going to show a cell loss that's greater than some critical amount.  Another way to ask that is what proportion of patients are going to have cell densities less than 1,000 to 1,200 in 10, 20, or 30 years. 

            Again, it's hard to answer with much confidence because now we're not just extrapolating the mean.  We are trying to extrapolate the percentiles.  We want to know what's the lower 10 percent of the patients and where are they going to be in 10 years.

            The best I can think of with the data we have is to take all the patients that we actually have.  We can actually fit a regression.  We have more than two observations on them, more than two follow-up visits.  We can fit a model that actually gives each of them the possibility of having their individual rate of loss. 

            The model actually is called random effects regression.  What it does is assumes that the losses come from some normal distribution so the rates of loss are coming from a common distribution.  That's what you see here.  These are the results.  The dark lines indicate the 1.5 and 2.0 percent losses.  You can see that most of them are below 1.5.

            So also using that same histogram we can save the percentage of patients with annual losses worse than a particular amount what can we expect.  Using these data and this model you can say that probably 5 percent of the patients are going to have losses of 2.2 percent or more, 99 percent of 1.5 percent or more.

            Again, I need to give some comments on these estimates because they are fairly highly dependent on the model used to arrive at the individual patient estimates.  The model, on the one hand, reduces the variability because it shrinks the estimates.  The estimates for each patient are moved toward the overall mean so that reduces the variability and that would tend to make this number a little bit smaller.

            On the other hand, the annual loss in this model where I didn't do the imputation was a little bit higher so that would tend to counteract that to some degree.  This is the most I can give you right now.

            Just to summarize, if I can, in one slide, the estimated annual loss is apparently about 1.8 percent per year with a 90 percent confidence interval 1.3 to 2.2.  For individual patients maybe a third of them have annual rates of loss more than two and five percent have rates of loss more than 2.2.  Again, it is necessary to do some form of long-term extrapolation but you need to try to interpret that with whatever amount of caution you want to put into it.  Thank you.

            DR. LEPRI:  Okay.  I'm going to present question 1 to you and then there are several slides of background data that you need for consideration.  You have the copies in front of you.  I'm able to put all of those charts into a slide form so you may want to refer back and forth to them.

            The first question is:

            1.  Do the endothelial cell data presented above by overall analysis, stratified by anterior chamber depth and the extrapolations over time provide reasonable assurance of safety of the ARTISAN myopia lens?

            Here is the data that was presented and the hardcopy questions that you have in front of you.  The first slide shows the estimated changes in cell loss at six months, one year, two years, and three years.  The standard deviations, errors, and confidence limits. 

            The next piece of information that you are to use is the percent change from baseline.  It shows also for the intervals of six months through three years.  The percent change by period, the difference between six months to one year, one year and two years. 

            In this slide it shows that in a paired analysis the percent change calculated between baseline and three years post-op was -4.76 percent with a standard deviation of 7.8 percent.  When analyzed by interval one can see that losses appear to be higher between the second and third postoperative years.

            The sponsor did show that when they eliminated the one site, that all had the specular microscopy done with the same device, when they had changed employees midstream during the study when they removed that data out, that dropped from -2.37 percent to minus 1.68 percent.

            DR. WEISS:  I would just request whoever has the cell phone if they could silence it forever.  Thank you.

            DR. LEPRI:  The next slide shows the endothelial cell count change over time from baseline stratified by anterior chamber depth for the 3.0 to 3.2 mm anterior chamber depth.  You can see the changes over time.  Even though the ends are small, there is no statistical significance to this but we want it for consideration for potential trend.

            The next slide is endothelial cell count changes from six months to three years stratified by all of the anterior chamber depths in the study.  The last slide is the subjects with three and four-year follow-up having that mean ECC at pre-op of 2754 with an end of 27 to show what their changes were from three to four years.

            2.  Do the other data presented in the PMA outside other endothelial cell data provide reasonable assurance of safety?  Those are to be considered as two separate issues. 

            This is the background for Question 3. The proposed statement of indication reads:  "The reduction or elimination of myopia in adults with myopia ranging from greater than -5 to less than -20D with less than 2D of astigmatism at the spectacle plane; Patients with documented stability of refraction for the prior six months, as demonstrated by a spherical equivalent change of less than or equal to 0.50D."

            3(a). Does the panel recommend any modifications to the proposed statement of indications with respect to:

      a). minimum anterior chamber depth;

      b). maximum pupil size (the 2 models of the ARTISAN are intended for patients with pupil sizes up to 5.0 mm and up to 6.0 mm; and

      c). minimum preoperative endothelial cell density?  The outcomes of ECC changes reported in the background data for question No. 1 above should be referenced if the panel wishes to recommend an acceptable minimum endothelial cell density to quality a patient.

      4.  Do the panel members have any additional labeling recommendations?

            DR. WEISS:  Thank you very much.  We are actually doing fairly well on time so what I would ask is if the -- I hear chuckles.  I guess usually we haven't been in the recent past.  What we're going to do is if the FDA could perhaps entertain some questions before lunch and I'm going to ask if anyone from the panel has any questions.

            DR. BRADLEY:  I have a quick question for Dr. Gray.

            DR. WEISS:  By the way, I wanted to thank Dr. Gray for that wonderful first slide showing where people fell out in terms of participating and not participating in specular microscopy because that really just clarified things amazingly.

            DR. BRADLEY:  Dr. Gray has presented a similar presentation some time ago, if I recall, to this group.  In both presentations you have admonished us to be very aware of the shortcomings of extrapolation.  In spite of that, we go ahead and extrapolate primarily because most of us are not very sophisticated.  I think you always give us a linear model which we can sort of understand because we can all draw a straight line with a rule.

            But in the end, from my perspective as a scientist not involved in this field, I just find myself incredibly uncomfortable with this extrapolation and I wondered do you know of any data from some other product, other condition that indicates that the pattern of cell loss seen in the first three years is, in fact, continued on in a linear way over five, 10, 15, or whatever years?  I don't know this field at all and maybe you could help.

            DR. GRAY:  Well, first of all, you might have noticed that I said in this presentation that some amount of extrapolation is necessary to make a decision.  Even though it's my job to warn you about it, you still have to do it. 

            In terms of further data that might corroborate any kind of model, all that I know about is what we presented in the 19-patient European cohort.  I actually, if you really want to see it, I have a plot somewhere.  If you plot those 19 patients superimposed on the extrapolation, they basically cover the whole range of error for prediction of an individual.  They are right there.  There's only 19 of them and when you look at that they have a fairly large amount of variability so it doesn't really help us to decide sort of a relatively subtle difference between something like a linear loss or an explanational loss or something like that.

            DR. BRADLEY:  Thank you.  I'll open the question up to anybody else in the room who is knowledgeable in the issue of endothelial cell count data.  Are there any data for some other product, some other disease that we have long-term data on?

            DR. WEISS:  Dr. Grimmett.

            DR. GRIMMETT:  Dr. Michael Grimmett.  In my review of endothelial data for this panel perhaps a year ago, the only other data that I could find would be Bill Bourne's data.  His data had several limitations in that the patients that had the cataract surgery had a wide variety of the types of procedure whether it be extracap or intracap. 

            Specular microscopy images were not standardized.  I don't believe that the Konan machine was around at that time.  I didn't go back through the data to look at it year by year to answer your question did the first three years actually predict what happened 10 years later.  That's the question you're asking.  But his data was such small numbers and such a wide variety of procedures that I'm not sure that would actually even looking at his data would actually answer it.  From my review I'm not aware of another product where we have the answer to that question.

            DR. GRAY:  Here is the trial I was referring to where the red dots have the 10-year European data.  You can see they neither confirm nor deny anything about -- their variability is fairly large here in these 19 patients and so they don't really tell me that the model is terribly wrong but they don't help me distinguish between fairly subtle differences.

            DR. WEISS:  Dr. Huang and then Dr. McMahon.

            DR. HUANG:  I know we spend a lot of time on endothelial cell counts from the FDA as well as the panel reviewers as well as the sponsor.  I would like to look at this problem with a little bit slightly different angle.  Truthfully that the cornea function is not really predicated on the absolute number of the endothelial cells. 

            It's really their functions.  So are we looking at the cells as indicative of function or should we just look at the cornea thickness as a function to see if the cornea retains integrity because clinically we have seen many patients with endothelial dystrophy with reduced cell count but over the years they don't have any cornea decompensation.          Even though the cell number continues to decrease, that doesn't mean the cornea is decompensating.  That is my concern about all these number calculations.  I understand that we need to have safety guidelines but, on the other hand, that's the only safety guideline that we need to be concerned about cornea integrity.  Thank you.

            DR. WEISS:  I think the difficulty will be that the cell count is going to be much more sensitive, perhaps not totally significant, than the corneal thickness because as we all know as corneal surgeons, the thickness or the cornea will decompensate at a much lower cell rate. 

            If you are a 20-year-old patient and let's say you're losing your cells at 3 percent per year, and it's linear and continual, then we would obviously have concerns at some point.  You may get into the risk of having decreased corneal function.  These are all very difficult questions because I think what we're being told by FDA and by sponsor we have a 1.7 to 1.8 percent corneal endothelial cell rate loss in the first three years. 

            It doesn't stabilize.  What we all know is the only time this will become significant is many, many years down the line past when hopefully all of us will be retired at that point and not meeting at this panel meeting but we need to project into the future with data that we don't have.

            Dr. McMahon.

            DR. McMAHON:  This goes back to Dr. Gray.  This might be extraspeculative but in that European data is it possible to use a nonlinear model?  The issue here is there a decrease in the rate of change at the end that would show some flattening?  I mean, the plots that you show demonstrate that these individuals if this is real are doomed if they live long enough.

            DR. GRAY:  It's possible to fit a nonlinear model but it's impossible with the data we have to distinguish between a linear or a nonlinear model.  We can do those fits if you want to extrapolate in some other way with some other model, you can either make it curve one way or the other and look either better or worse.  I have no basis based on the data we have to pick one of those models over the other. 

            What I present here is just the straight line middle-of-the-road linear extrapolation.  If you have some reason to choose otherwise, we can entertain another model.  It's difficult.  It's impossible with the data we have, I think, to distinguish between those.

            DR. WEISS:  Any other questions from panel?

            DR. BRADLEY:  Sorry, Dr. Gray.  You stepped down.  I'm still not clear on what you've shown us here.  The red dots --

            DR. GRAY:  Is this on?

            DR. BRADLEY:  Let me get my question out and you can answer it.  For example, these are 10-year follow-up.  Presumably these people at this time are 10 years older and one wonders what the age match norms might be for this group.  That looks to me like most definitely the means must be lower in this sample that you put up there, the 10-year follow-up. 

            I wonder how different are they to age-matched controls, age-matched norms, for that group of people whatever age they were.  I'm trying to get a sense does this group really have lower than normal looking endothelial counts.  That wasn't a very clear question.  Sorry about that.

            DR. GRAY:  Well, first of all, let me make it clear that I did not do -- these red points were not included in making this fit at all because I didn't -- I don't have enough information to have any idea whether we can pull together the data and use them in the same model or not.  This plot was only made just in case we wanted to see how it looked instead of looking at the figures that I presented in slide No. 10.

            Again, all I had, I personally got these data last week so I didn't have a lot of time to fiddle with them.  All I had was the -- I don't have the co-variates.  I don't know their ages.  I don't know anything about them.  I don't know the pupil diameter, none of that stuff.  All I know is -- all I got was the counts at baseline and the various follow-ups. 

            In the 10-year European, the slide that had that was just to indicate it.  This is all we really know about long-term.  This is the best we have in terms of long-term follow-up.  This plot is just another way to look at that to see if there was some obvious red flag that any kind of extrapolation was off the mark.  Really what the plot tells you is that there's not much information here.

            DR. WEISS:  Dr. Mathers.

            DR. MATHERS:  Bill Mathers.  What you're saying is that those red dots are actually extraneous to this graph.  They happen to fall right down the middle where the extrapolation is which would mean that the extrapolation seems to be consistent with the 10-year data of the European but, of course, you can't really say that.

            DR. GRAY:  I would say it's not inconsistent.

            DR. MATHERS:  It's not inconsistent.

            DR. GRAY:  I'm a statistician.  But also there are some patterns in the European data that are different than the data we see here.  For example, 353-eye cohort that we looked at there was virtually no change between baseline and the six-month follow-up which is counter to anything I have been led to expect. 

            Whereas for this European cohort there was a six percent loss between baseline and six months.  So the patterns even though it comes out the same in the end at the 10-year point.  The patterns up here at the beginning are somewhat different.  Who knows if it's just due to the few number of patients or that they are really different patients.  The population is somehow different demographically.  I don't have that information.

            DR. MATHERS:  But to the subjective eye it looks like those red dots were used to calculate it because they look smack on.

            DR. GRAY:  They do but you will also remember that I mentioned I think it's three or four of them above the 90 percent line and four or five of them are below.  They actually have a fairly large amount of variability compared to the line that we do have. 

            I don't know how they got these counts.  I don't know how the counts were standardized or anything but the amount of variability is actually fairly large here compared to what we had seen before in the current data set.

            DR. WEISS:  Is there a zero timeline for the European data?  We have it on the 10-year.

            DR. GRAY:  If you look at slide 10 at baseline, there was 2,666 which was 100 cells lower than the mean and about 100 cells lower than the 2,760 in the current cohort so they started out slightly lower.

            DR. WEISS:  So just following up with what Dr. Mathers is asking, if that was plotted out there, would that fall quite similarly with the black line?

            DR. GRAY:  If you look at --

            DR. WEISS:  That would sort of correlate with what Bill is asking, that if it looks similar at zero and it looks similar at 10, then maybe it actually --

            DR. GRAY:  The change --

            DR. WEISS:  Maybe it's not inconsistent with being similar.

            DR. GRAY:  Actually, the change for the -- I didn't want to make too much of -- we only have 19 patients and I don't know much about them but, having said that, for that cohort the average loss between six months and 10 years, the annual rate is 1.2 percent.  It's actually lower than what we saw in the PMA cohort.

            They had a very large drop at the beginning and then they leveled out somewhat.  If you look at slide No. 10 it has a whole bunch of different ways of looking at the data to try to help you make some sense of that.

            DR. WEISS:  In the European data they only had 19 patients and there was a large amount of variability so all of these are deficits of over analyzing this data.  Having said that, they have a 1.2 percent cell loss rate.  Okay, good.  From six months to 10 years.

            DR. GRAY:  They had a fairly high rate of loss between six months and three years, 2.9 percent.  It was high.  And then between the two time points, three years and 10 years, it dropped off to 0.7 percent.  If you are optimistic you say the long-term rate is close to normal.  If you are pessimistic you say the initial rate in the first three years was quite high and I don't really believe -- there's not enough data here to really tell what is going on so it's a judgment at this point with those 19 patients in my opinion.

            DR. WEISS:  Dr. Macsai.

            DR. MACSAI:  Dr. Gray, can you address something about this slide?  I thought enrollment criteria was 2,000 cells or above.  On the slide at the zero there's a whole bunch of little points.  Maybe it's my refraction.  I can't see how many little points but they are below 2,000.

            DR. WEISS:  You need to get an ARTISAN.

            DR. MACSAI:  My contrast, I think.

            DR. WEISS:  Sorry.  Getting close to lunch.

            DR. MACSAI:  It seems like there are little dots on your graph below 2,000 at baseline.

            DR. GRAY:  There are.

            DR. MACSAI:  How is that possible?

            DR. GRAY:  Well, it looks to me like there's four or five dots below baseline at 2,000.  You will recall that these are the recount data.  These are not the initial counts so it could have been that when the patient was enrolled whoever did the endothelial cell count deciding it counted them one way, and you will remember there is a fairly large variability in the counting process so it's not surprising that a few of them actually came out lower when you recounted them.  That's why the new suggestion is three photographs per person and standardization of the counting procedure to try to minimize that kind of variability.

            DR. MACSAI:  So we're not even 100 percent certain that our baseline counts, because these are based on one picture where all of those below 70 were kind of thrown out and we don't even know if that amount was thrown out was randomly distributed or skewed in some way.  We don't even know if our baseline is right is what you're saying in a statistical manner.  I mean, where you don't want to be committal but that's what it sounds like.

            DR. GRAY:  What I'm saying is the sponsor had a slide that talked about the about of variability in the measurement of the endothelial cell density.  There actually is inherent in this whole process a fair amount of variability.  We take photographs of some location in your eye that can vary.  Some of the photographs turn out good or bad for whatever reason and then we have people trying to count and to obtain a density, a cell density. 

            Just that whole process has a fair amount of variability in it.  When you say sure, we're not positive of any of these counts.  They have some measuring error.  The recount data have less variability than the original study.

            DR. MACSAI:  Based on what do you say that?  I mean, there's no standardization.  It sounds like there's no check and balance done before it started.

            DR. ROSENTHAL:  Can I just explain something?

            DR. MACSAI:  Yeah.  I'm really confused.

            DR. ROSENTHAL:  Their initial endothelial cell counts were done with large -- were not done in the standardized way.  They were all over the board when it came to the variability.  The Agency asked them to go back and to try out of this large number of eyes to get those that were taken standardly, were counted standardly, and were evaluated standardly.  It's the best, frankly, I think we can do particularly when a new modality to look at the endothelial cell counts came up in the middle of their study.

            DR. WEISS:  Dr. Schein.  Sorry.

            DR. ROSENTHAL:  They were all using different methods of doing it.

            DR. WEISS:  Dr. Macsai wanted to follow up and then Dr. Schein and then Dr. Grimmett.

            DR. MACSAI:  I feel an obligation here to make a follow-up statement, Dr. Rosenthal.

            DR. ROSENTHAL:  Sure.

            DR. MACSAI:  I believe that the Konan specular microscope was available in 1997.  Whether or not someone chose to utilize it it existed.  Let's not preclude that it came about in 1999.  That's point No. 1. 

            Point No. 2, from our history as ophthalmologists knowing the complications of anterior chamber intraocular lenses in patients, the Lysky, the ORC, when we designed these studies using an ACIOL I think it behooves the sponsor and the Agency to address these critical issues at the beginning before we move forward with implantation in patients because now we're looking at maybes.

            DR. WEISS:  Dr. Rosenthal.

            DR. ROSENTHAL:  I have to stick up for the Agency a little bit.  I think in 1997 there was not as great a science of endothelial cell count as there is in the past three or four years.  Certainly working on it in the standards group it was a very contentious issue and it took a long time to come to some conclusion how best to do it. 

            I don't know if Donna wants to comment on that.  When a company puts together a protocol for an IDE, we have to use what is currently considered the best science.  Frankly, the science of endothelial cell counts in 1997 did not have a quality standard.

            DR. WEISS:  That will be the last word on that subject.  I would like to go back to questioning.  We just have a few minutes right now.  Dr. Schein, if you have anything that you -- a question as opposed to any comments.

            DR. SCHEIN:  You've taken a comment right out of my mouth but I have one last question for Dr. Gray.  Putting the cornea aside for the moment, I'm interested to know if you did any time dependent analyses of other complications, development of lens opacities, need for cataract surgery, intraocular lens or lens exchange, retinal detachment, etc., etc., both within the time frames of the data that you have and an extrapolation into the future.

            DR. GRAY:  The brief answer to that is no, I didn't do any of those analyses.

            DR. SCHEIN:  I would suggest they might be useful if for nothing else than patient education to describe whether if you survive the first month or year or 18 months, that the complication rate goes down dramatically or the converse obviously equally important.

            DR. WEISS:  Fifty seconds.

            DR. BRADLEY:  Dr. Bradley.  Again, Dr. Gray, question from your analysis.  Did you notice whether the cell-loss rates correlated with the initial cell count.

            DR. GRAY:  As far as I could tell they did not.  There was no significant indication that the rate of loss was a function of the baseline count.

            DR. BRADLEY:  So would the appropriate interpretation of that result be those with the low initial cell counts are at the greatest risk?

            DR. GRAY:  Yeah, I would say that's a fair interpretation of that. 

            DR. WEISS:  Depending on how long --

            DR. GRAY:  As far as I recall, there was not -- it's difficult to work with the data when a lot is missing like this but I couldn't find any association between the baseline count and the rate.  As far as I can tell the best thing to do is just assume that it isn't a function of the rate and if you are low to begin with, you're at a higher risk.

            DR. WEISS:  Thank you very much.  12:30.  We'll break for lunch for one hour.

            (Whereupon, at 12:29 p.m. off the record until 1:36 p.m.)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

         A-F-T-E-R-N-O-O-N  S-E-S-S-I-O-N

                                         1:36 p.m.

            DR. WEISS:  Okay.  So what I would like to do before we go to -- we are going to be starting -- before we start committee deliberations, I had one question for the FDA which was on the basis of their presentation if they any recommendations as far as a time point after lens implantation, which would make it much easier to extrapolate, the endothelial cell count some years down the line as opposed to having to wait 20 years to find out what the answer would be in 20 years.  I don't know who would be able to answer that one for us.

            DR. GRAY:  I can give you my opinion on that.

            DR. WEISS:  That's the one we want.

            DR. GRAY:  What you're trying to do is extrapolate 10 times the range of the data that you have.  That makes any kind of distinguishing between

-- several models could probably fit equally well within the relatively short amount of time you have, three, even if we have four years, and still be fairly divergent after 30 or 40 more years. 

            It's going to be very difficult in terms of extrapolating out 40 years and know anything until we do get to the 10 or 20-year point.  That's obviously somewhat impractical in terms of making a decision about approval. 

            Every year helps.  Every year that you have further on that has no obvious increase and perhaps a decrease the better off you are.  You are never going to be able to prior to approval have enough data to definitively say that it's one particular kind of functional form as far out as you want to go.endothelial

            DR. WEISS:  So from what I understand you to say that if we have four-year data or five-year data, that would not make the answer anymore clear than having three-year data.

            DR. GRAY:  In terms of the extrapolation I don't know that it would make that much difference in terms of distinguishing between a straight line and a curve, something like that.

            DR. WEISS:  Okay.  Thank you. 

            There were a few questions that we had asked sponsor to look up.  I'm told they have the answers to some of these.  If they could come forward.  There was a question I had about pupil size and explantation and a question that Dr. Casey had and Dr. Smith had.

            DR. STULTING:  Thank you, Dr. Weiss.  We worked on this during the lunch break and I'll share with you the data that I have.  There may be some more available later in the day.  One of the questions that I may note of was the issue of mesopic pupil size and lens optic size.  The sponsor did a multi-variate analysis looking at the presence of visual symptoms at night looking for correlations. 

            One of the correlations that they sought was mesopic pupil size greater than the lens optic size.  In the cohort there were 56 first eyes enrolled and 31 who answered the questionnaire who fit this criterion.  There was no correlation found in that analysis.  I don't have power calculations available.  That is something we can get for you later.

            The second question that I made note of was some concern about the possibility of bias in the selection of recount patients.  I want to spend just a minute going over the protocol that was used to select those eyes.

            The selection of sites for the recount was based only on the availability of instrumentation.  It is possible that there is some unrecognized bias that people who are particularly good surgeons happen to have particularly good specular microscopes or something like that that we can't definitively and absolutely rule out, but there was no intent for that.

            All available readable images regardless of endothelial cell morphology were included.  In fact, this was a masked selection.  The images were read -- were obtained and read at a central center not knowing who they belonged to, whether they were preoperative or postoperative, etc.

            Once they were read, then a minimum of two readable images at different time points was required in order for an individual to be a member of the recount study.  The other question that was related that was asked was how many images with only a few cells were eliminated?  The answer to that is there were 12 poor quality images eliminated because there were less than 70 analyzable cells in those images.

            Those were the exclusions among 1,156 images that were analyzed leaving a total of 1,144 images which formed the data set that the recounts were derived from.  We believe that the elimination of these few images probably didn't have anything to do with the results.

            The third question was endothelial cell counts for Group E.  Remember Group E was the group with replacement intraocular lenses, previous corneal transplants, custom made lenses that were fabricated with powers outside of the usual range, best corrected acuities less than 20/40.

            Nine of these were included in the recount analysis.  Three of them had replacement intraocular lenses.  Two of them had custom lenses.  Four of them had best corrected acuity of less than 20/40.  There were 23 observations in this group so it was a relatively small group and in these there was an average loss of 2.67 percent per year.  Recognize that one-third of these were people who had had an extra surgical procedure to remove the intraocular lens. 

            A question was asked about endothelial cell count reliability.  I answered it by saying that the protocol did not have any internal controls for reproducability.  However, I would like to share with you some data about endothelial cell count reliability since the question was asked.

            Once the images had been obtained, screened and read at a single trained central center, those images -- 50 of those images were randomly selected and sent to another reading center.  This is a center that was outside of the investigational sites and a center that most of you would probably recognize that normally does endothelial cell counts.

            So these same images were read by the second center.  This then is a test of reproducability of reading alone because they were exactly the same images.  The differences un the mean cell counts in this exercise was 0.8 percent, not significantly different from zero.  But the standard deviation was relatively large, 24 percent, ranging from -47.2 to +48.8 percent and 28 percent of these readings showed a more than 10 percent loss or gain.  So this speaks to the ability to read these images. I speaks to the reliability of the methodology for endothelial cell counts.

            Remember that these cells -- we are only counting 80 to 100 cells in most of these eyes, mean 109 even with selected images.  If you are off by two or three cells, it makes a big difference in the calculated endothelial cell density.

            With regard to the labeling, I would just like to make a suggestion  and that is that we produce a graph something like this showing a calculated endothelial cell loss over time and relating the endothelial cell density to the age with endothelial cell density on the vertical axis and age on the horizontal axis using our best data available with the best projects of time so that I as a consumer, as an ethical physician, can have this information knowing that it would be best to implant or not implant depending upon these parameters.  Thank you.

            DR. WEISS:  Thank you.  We're going to go on with the primary panel reviews.  Dr. Mathers.

            DR. MATHERS:  Thank you, Dr. Weiss.  Bill Mathers.  I will relate to you my primary review.  The application concerns a lens that is designed to correct myopia, moderate to high degree, five to 20 diopters by means of a lens device that is inserted into the anterior chamber and clipped to the anterior surface of the iris which maintains it's fixation and it's centration. 

            The highly myopic population has significant problems with spectacle correction.  Contact lens are usually the preferred method of correction for this group if they are tolerated.  Subject with dry eyes, surface disease, and other difficulties that preclude contact lens wear have few options.

            We are given the question for the panel discussion, "Do the endothelial cell data presented in the overall analysis stratified by anterior chamber depth and extrapolated over time provide reasonable assurance of safety for the ARTISAN myopic lens?" 

            There are several safety considerations that need to be addressed.  The primary and overriding issue, however, is, I believe, the question of endothelial cell loss over time and the change in endothelial cell density resulting from the insertion and retention of the lens.

            Data supplied by the applicant is presented in two forms, for the whole group and for smaller subgroups stratified by anterior chamber depth.  For the whole group the endothelial loss rate for three years, the duration of the study was 4.75 percent and this is a loss rate of 1.58 percent per year with an  N of 111.  I realize my numbers are not exactly the same as some others that we've heard but I believe actually they have come up pretty close.

            This contrast with the loss rate in the normal population of .6 percent and a loss rate of 2.5 percent for 10 years following cataract surgery.  This cumulative endothelial loss is highly relevant to the younger population for which this lens is primarily intended.  The table below indicates the resulting endothelial cell counts that could be expected if the loss continues at this rate for 10, 20, 30, or 40 years.  I realize you may not have that in front of you but I'm going to go over the numbers.

            Starting with 2,754 cells per square millimeter the mean endothelial cell density may seem reasonable but half the group will have an ECD less than this.  The applicant has requested permission to use the device in 21-year-old subjects with an ECD down to 2,000.  The main corneal clarity usually requires -- to maintain corneal clarity usually requires an ECD of 800.  These are rough figures but they are probably correct. 

            For a reasonable margin of safety an ECD of 1,200 would be a better cutoff and even this is fairly low.  Starting from the mean ECD and the lowest cell loss rate the average subject would be at risk after 40 years.  Subjects with an initial ECD of 2,400, usually considered to be quite good cell count, would reach the point of risk at about 30 years. 

            If the subject had an ECD at the low end of 2,000, the 1,200 end point would be obtained in 23 years and the 800 ECD would be reached before 40 years.  A cell count of 1,200 does not guarantee imminent corneal failure but there is definitely an increased risk at this point.  One needs to consider that these patients at that time are going to be facing cataract surgery which always has some consequence for the endothelium.

            The data actually shows that the estimated loss rate from six months to three years, which is a total of 30 months, if this data is correct, then the loss rate is more like 1.9 percent per year.  The resulting calculations shown above indicate that even starting with relatively high ECD of 2,754 the final ECD reaches 1,200 prior to 30 years.  By 40 years the endothelial cell count is so low as to guarantee failure.

            These calculations are based on a mean loss rate.  Also given our 95 percent confidence internal which have a high-end loss rate of 6.1 percent for three years, or 2.03 percent per year.  At this rate the 1,200 ECD is reached in about 26 years starting from the high end of 2,754. 

            Five percent may fall beyond this range and an ECD of 1,200 reached sooner than that.  Starting from an ECD of 2,000, which they are requesting, the 800 level is reached before 30 years.  I want to point out here from today's discussion that Dr. Gray's assessment at 38 percent of the population could be expected to have a loss rate of two percent which is a failure rate, or 1,200 rate at only 25 years.

            The highest loss rate was found in a group with an anterior chamber depth of 3 to 3.2.  For this group the loss over three years, or maybe 30 months, I'm not sure, was 9.16 percent or 3 percent per year.  This is a loss rate that is approximately double the group as a whole.  Thus, the time to reach 1,200 or 800 is half the original calculation.

            From an ECD of 2,000 less than 20 years would be required to reach 800.  These calculations assume that the endothelial loss is close to the mean.  Unfortunately, this is not likely to be the case since the standard deviation reported in the revised application is nearly twice the mean number.  This indicates that some subjects will likely experience a substantially more rapid decline in their endothelial cell density than these calculations show.

            This device is currently marketed in over 40 countries and the report states that the device has not been removed from any of these for any safety concerns.  This is not surprising because the time to achieve is sufficiently low ECD that would create corneal edema is still always over 15 years.  Our 10-year data given to us before and also reanalyzed today I would think does not contraindicate or contradict this conclusion.

            The endothelial cell losses are mostly less than those that have been reported for cataract surgery.  A comparison with cataract surgery is relevant since clear lens extraction is one alternative that some practitioners use to correct extreme myopia.

            For both operations there is a small incision into the anterior chamber and the device is implanted.  Surgical trauma and postoperative inflammation could be expected to be of a similar range. 

            Cataract surgery is extremely common and the risks are generally considered to be low and reasonable.  Why is this different here?  The age of the cataract surgery population is higher and, thus, the postoperative duration is much longer for the ARTISAN myopic lens. 

            In addition, preoperative vision loss is greater for the cataract group and the relative risk of surgery can be correspondingly greater.  Finally, there are alternatives to phakic lens implants, whereas a cataract patient requires the replacement of the lens to restore vision in this new alternative.

            Other safety concerns of shorter duration, less than 5 percent of subjects lost two lines of best corrected vision and 100 percent at three years had a best corrected of 20/40 or better within 228.  This is in the range of cataract surgery where severe vision loss can be expected in the 1,000 to 2,000 or less range. 

            One subject was developing PSE cataract and we heard some other issues about cataract formation today that I'm not quoting.  There was one case of a macular hole.  Over time the incidence of cataract may be higher because of subclinical inflammation from the lens. 

            But the rate of cataract development in this group is already higher than average and it will very difficult to make this attribution accurately.  Postoperative inflammation in the form of cell and flare is persistent in 1.3 percent of subjects at six months. 

            This chronic inflammation may contribute to the cataract formation later.  Corneal edema was surprisingly prevalent at 20 percent on day one and this dropped 2.2 percent in two weeks but I think this level is acceptable.

            Regarding accuracy issues, the accuracy of the implant appears to be excellent considering the very great difficulties in determining chamber depth and refractive error and high myopes.  Cataract surgery shows us that this can be actually quite hazardous to predict accurately.

            Manifest refraction spherical equivalents were very good as 71.7 percent to 76 percent had an MRSE within .5 diopters of the target after six months and 93 percent had within target with 1 diopter at six months.

            The majority of subjects gained at least one line of best corrected vision which is quite remarkable.  Visual side effects, glare and halos could be expected to occur if light passes outside the limits of the lens and enters the eye through the large pupil.  This should occur primarily at night when the pupil is largest. 

            Such issues are real but of lesser concern since many of the subjects already experienced such visual symptoms without the lens in place.  Severe glare was noted at one percent at all post-op visits.  Halos were more common and were moderately severe in 17 percent and severe in 3.5 percent.

            Regarding the assessment and recommendations, question 1 and 2, it is my opinion that the lens is not safe for the currently intended subject population.  Endothelial cell loss is a progressive problem.  The damage from ongoing cell loss could be partially ameliorated by requiring the pre-op cell count of greater than 2,400, or perhaps some other number. 

            This would not completely solve the problem but it would help.  It would also help to limit the age of the subjects.  Those between 21 and 50 have different needs and issues compared with the older group. 

            It would be wise to be the most stringent with the younger group.  The reviewer believes this lens is not safe to implant in subjects under the age of 35 regardless of the cell count.  For those between 35 and 50 a cell count of at least 2,400 should be required.  This would delay onset of the mean risk point, an ECD of 800 to age 75.  Keeping in mind the wide 95 percent competence interval and the large standard deviations revealed in the data, this seems a reasonable level of risk.

            As an alternative or additional method to reduce risk, the reviewer recommends the panel consider limiting the lens to those most in need, the group with a refraction of 9 diopters or greater.  For this subset the alternatives are very limited and the added risk of late complications may be more reasonable.

            For subjects over the age of 50 the late complications, 30 and 40 years away, are less threatening even though there was a real probability that they will live -- these subjects will live into their 90s.  For this group a pre-op ECD of 2,000 will still probably lead to failure in 30 years.  This is, nevertheless, a reasonable risk that is in line with clear lens extraction or with early cataract removal, two likely alternatives.

            There seems to be a very compelling reason to limit the lens to those with an anterior chamber depth greater than 3.2.  For an anterior chamber depth less than this, endothelial cell loss was twice as high and clearly unacceptable at any age or ECD.  I believe it is reasonable that the lens diameter should be limited to the size of the dark-adapted pupil, although I understand that the correlation of halos and glare is not very good and has some other considerations.

            That concludes my remarks.  Thank you.

            DR. WEISS:  Thank you, Dr. Mathers.

            Dr. Schein.

            DR. SCHEIN:  If I can make this work, I'm just going to present an overview of the comments that I submitted several weeks ago.  I'll try to move quickly through anything that's been pretty well covered already.  I'm purposely not going to address the individual questions at the end but to make some more general comments that I had in reviewing the protocol.

            I had some frustrations in reviewing it because I felt that the work was all there but I couldn't quite extract it in the way that I needed to in order to make the assessments regarding safety that I was trying to. 

            First let me make a few general comments.  I believe there is consensus that some follow-up of reasonable length is needed to determine safety.  In the cohort I examined, we only have three-year data on about a third of eyes.  It makes it hard to think of complications rates after that distance.  It's greater at two years, I understand, but perhaps only about 60 percent at that time.  I'm not going to get into protocol violations since we discussed that a lot this morning.

            There has been a repeated theme which I would like to emphasize.  When we're looking at safety, I would like to know safety not in some subgroup of patients, this Group A.  I would like to know safety across the entire cohort that underwent the implantation of the device.

            Obviously it would not report efficacy in a group, particularly efficacy related to corrected acuity in individuals who didn't meet a standardized entry acuity level but I do want to know this for adverse events.

            There were, for example, about 50 eyes which were excluded from that primary analysis of Group A who appeared to have about twice the adverse event rate as defined by the sponsor.  Likewise, I would like to look at safety issues or complication rates that in some way reflect the duration of time in the study. 

            For subjects that are lost to follow-up, there was a table which I've referenced there where about 20 percent of them have some worrying anatomical or functional feature noted on the last exam recorded.  Of course, these are patients that are excluded from the two or three-year rates of complications.

            Another issue is I would like to see adverse events and safety talked about presented not just on a per-eye basis but on a patient basis.  Certainly a patient who has a retinal detachment on one eye would view the procedure as risky even in the presence of one eye that didn't have such a problem.

            The intent of this device is as a bilateral device and ultimately it will be used almost exclusively as a bilateral treatment much as contact lenses are used.  So similarly at different places in the report there are different rates that were given.  A quoted a rate of 3.4 percent, again, is not on a person level.  It's on an eye level. 

            It's not accounting for variable length of follow-up so in these three year cumulative rates where a denominator of 662 is quoted, I don't know how to -- I don't know what inference to draw from that when I have less than one-half the potential data at three years in hand.

            There are references throughout the PMA and in the proposed labeling for comparisons with anterior chamber intraocular lenses.  I think there may be historical reasons why these are in the document but I think they are inappropriate comparisons since patients undergoing anterior chamber intraocular lens are typically older.  They are often already aphakic or they are in the process of suffering complications from cataract surgery, not a good comparison to make.

            Looking at the safety issues, again, trying to figure out what the rates were, I had more difficulty trying to understand the differences between what were termed complications and/or adverse events.  Lens opacity was listed as a complication but not cataract extraction.  That seemed to be listed under other procedures.  I found a couple under lens exchange. 

            The resuturing of a wound leak in the early postoperative period was called a secondary procedure.  In my cataract practice I would call that a complication.  It's not the same as a secondary refractive procedure downstream to make more accurate the efficacy of the procedure.  So there's inconsistency.  Retinal detachment is a complication not listed as a secondary procedure.  Again, all presented on a per-eye basis alone.

            I would propose that complications be divided in analyses into those which have clinical significance with an obvious potential to cause harm and I've labeled a few of them here.  There are others.  And to distinguish those from I would call more trivial events such as the need for punctual occlusion or the need to widen a peripheral iridotomy.

            The labeling of activities like needed to resuture or reposition an intraocular lens as a nonadverse event makes no sense to me clinically.  Again, frustrating in trying to figure out what the true rates of adverse events actually was.  Let's try to separate the things of clinical importance from those which are not.

            Similar, this issue of something parsing events that might be potentially avoidable versus not.  I have even more trouble since I see no way to divorce the device itself from the surgical procedure that accompanies it.  The material is polymethymethacrylate and is fine and inert.  It has a wonderful track record but you cannot separate the two of them.

            There is a presumption that the device and retinal detachment or, for that matter, development of cataract may be unrelated and that these are high myopes who are going to get these complications anyway.  In the absence of a control group I think the sponsor takes the risk of a presumption of exactly the opposite. 

            The enrolled cohort here appropriately could not have had retinal detachment in the eye that was being enrolled either in the past year or in the past decade except for patients that were 30, 40, and 50 years old.  By definition having not had them even though they were at risk, this is a group that is in a sense a survivorship group whose anticipated rate of such adverse events over a one, two, or three-year period would be expected to be lower, not higher.

            So lens opacities, I believe, were recorded in about five percent of eyes but in the absence of a standardized grading system.  I think someone made the implication earlier that in 1997 there was no concern about an aphakic intraocular lens in development of cataract and no understanding that endothelial cell counts were problematic and required multiple testing, repeat testing no matter what the name of the device was.  I reject both of those notions.  These things were well known in 1997.

            It's difficult to assess.  I don't know whether it's five percent or one percent or 10 percent.  I am more concerned actually with the time dependent rate of cataract development than I currently am with projections three decades down stream for endothelial cell loss because as these patients age, they are likely to develop cataract, particularly if there is a risk of this device. 

            Such patients will have difficulties measuring the intraocular lens to replace and these patients will undergo cataract surgery combined with an anterior chamber lens removal which will certainly add to the risk of cataract surgery.

            Regarding patient-reported visual side effects depending on one's perspective you could look at this either as an efficacy or a safety issue.  In looking at it from the safety perspective, I focus on individuals who do not report the symptom before surgery and then develop it later. 

            It's very nice that there are individuals who report it before who do not have it later.  Again, from a safety public health perspective this is the group I'm most interested in and 15 to 30 percent developed symptoms of varying severity, usually not too severe but were ones that were not noted preoperatively.

            This is something that I think can benefit from further analyses to see whether there were subgroups, age, gender, degree of refractive error, the obvious kinds of parameters to see if there are subgroups with really, really large rates that would be part of a patient education or even a labeling issue.

            Finally, endothelial cell counts were left unfortunately with having to draw inferences from data sets each one of which, I think, has substantial problems and limitations.  Unfortunately, each data set does not compliment the other, at least in a meaningful way that I can see.

            I'm actually drawn most towards the full data set.  Although the image quality is poor, there is no reason to think there is a systematic bias towards under or over reporting.  About 25 percent of individuals seem to have lost 10 percent or more cells which was substantially more than the proportion gaining 10 percent or more cells.  I can't recall. 

            I think it was in the range of three to five percent that gained.  So if it were purely noise, I would expect an equal distribution.  Again, I couldn't tell from my own review how individuals who had secondary procedures or problems were handled or whether they were included or excluded.

            This we've discussed further.  Reanalyzing data reduces the individual variability but, as Dr. Stulting just point out, the measurements are still problematic because of test, retest or interpretation and reinterpretation variability.

            So we are left with non-US data.  The Canadian data is means only and I feel very strongly that looking at means is not the way to look at endothelial cell count again.  From a safety perspective we're interested in the worse X percent. We can argue whether it's five or 10 or 15 percent or 20 percent or more cell loss but it's that part of the distribution that you're worried about from the safety perspective.

            European data has all the problems that we've already discussed.  A third of the patients had lost 20 percent or more cells by 10 years but, again, I don't know how much faith to put in such a small sample.  I think it would be worth some discussion to get some consensus on how much of incremental loss would be of clinical significance. 

            We've talked about 1,200 being a floor but I reject having a rigid final cutoff because of the anticipation that a large number of these patients are likely to undergo cataract surgery and lose another five to 25 percent based on that last intervention.

            To summarize, I have concerns based on the data that's presented to date that is incomplete in comparison to what will presumably be collected over the next 18 months.  Additional analyses of the kinds I've recommended and the three-year data, in other words, without any new data collection on patients that haven't been recruited, I think, would go a long way. 

            Particularly to these nonendothelial cell count issues one would be able to see whether the rates of retinal detachment and cataract surgery, lens reposition opacities was actually on the increase or whether there were things that tended to occur early and then flattened out.  That would be very important to know.  Thank you.

            DR. WEISS:  Thank.  Dr. Macsai.

            DR. MACSAI:  Before I start, I would like to acknowledge -- I would like to thank the Agency for this opportunity to review this PMA.  I would like to acknowledge the sponsor's work in putting it together and the extraordinary analysis by Drs. Lepri, Gray and Calogero.

            In addition, I would like to echo some of Dr. Schein's sentiments.  This was a very difficult PMA to analyze.  It was difficult for a number of reasons but they mostly have to do with lack of standardization and probably protocol design.

            As I said earlier, I think that we need to look at this in light of what we know about anterior chamber IOLs and what are the risks of phakic IOLs wherever they reside within the eye.

            I submitted to the panel and to the Agency a long primary review which I know the sponsors received so what I would like to do is just highlight a few issues that I think warrant our review.  The first is that of accountability.  I felt the accountability of this PMA was moderate. 

            It dropped below 75 percent at the three-year exam.  Dr. Stulting did tell us patients were only told they would need to be enrolled for two years.  But what is of concern is that 53 percent of the subjects in this study are ongoing and perhaps we are looking at an incomplete data set. 

            Eleven percent were discontinued and of these that were discontinued we learned earlier some were lost to follow-up and others had problems with the device.  Those that had problems with the device are inappropriately grouped as discontinued.  They should be listed as complications or treatment failures.

            Enrollment.  Of the 684 subjects 184 subjects were enrolled with protocol deviations in one or both eyes.  This was discussed and apparently the Agency cleared these but, in my opinion, this is an alarming number of patients with protocol deviations.  If the protocol is set up by the sponsors, perhaps they were too rigid in their initial establishment of enrollment criteria.

            If you look at it this way, 25 percent of the subjects do not meet the enrollment criteria and this is making it even more difficult for us to analyze both the safety and efficacy of this device.  When we look at criteria for safety and efficacy to quote, "The rates of cumulative and persistent complications should not exceed those of the FDA grid for anterior chamber IOLs."

            I know this has been mentioned before but I have to go on record as saying this is not acceptable to me.  The safety criteria for a phakic IOL should not be compared to that used during cataract surgery for an anterior chamber intraocular lens.  In 2004, 1998, 1990 you used an anterior chamber IOL because things had gone wrong, disastrously wrong during cataract surgery. 

            In those patients an anterior chamber IOL was a second choice.  Why would we compare an elective procedure that's refractive to an acceptable grid for a second choice in the treatment of a pathologic condition?  The phakic IOLs must be held to a much higher standard than that of the FDA grid for ACIOLs.           If it is acceptable to some to make this comparison, then we have to look at the historical perspective of what has happened with ACIOLs in the United States and what has happened with numerous ACIOL designs, their effects on endothelial cells, the fact that most of the cornea surgeons at this panel meeting cut their teeth doing transplants and removing these anterior chamber IOLs.  

            We knew long ago about the risks of endothelial damage with the anterior chamber IOLs.  If we are going to set this PMA up as comparable to the FDA grid for ACIOLs, then I think we should also be very careful about saying that we in 1997 did not necessarily have knowledge of endothelial cell standardization or damage, etc.

            Dr. Stulting has gratefully produced some information about Group E which is the eyes not included in Groups A and B in which this was used compassionate use or custom made lenses or eyes that did not have a best corrected vision of 20/40.  This data really needs to be reported to the implanting surgeon and the consumers. 

            It's a very, very important safety criteria.  It's critical to know what happens when this lens is placed, for example, under a transplant or if it's a custom designed implants.  The consumer must have this information and the information needs to be segregated based on the power of the IOLs, the age of the patients, the reason that the patients are in Group E.

            Lens opacities.  Twenty-six of the eyes had preoperative lens opacities.  I said this at the beginning, they were not measured in any standardized manner.  If you can't measure them standardized preoperatively, you can't measure them postoperatively and I think a comparison is ludicrous. 

            You're comparing apples to oranges.  What's my opinion is different than your opinion as far as cataract formation in a lens.  This is not able to be scientifically evaluated with this lack of standardization.

            What about the safety of all lens powers?  Well, only three implants were placed under 7 diopters.  This is a very small end allowing for absolutely no statistical significance.  What about the role of corneal abnormalities?  It was very hard for me to figure out from this PMA what was defined as a corneal abnormality. 

            Was it Fuch's dystrophy or was it a little foreign body scar from contact lens wear?  I don't know.  Without that knowledge I can't tell if there is a skew in the endothelial cell count data that may result from including these 41 eyes.

            Adverse events.  The sponsor stated that they thought an adverse event of one percent was acceptable and here I will echo the comments of Dr. Schein.  You cannot arbitrarily decide what an adverse event is.  Anything that happens as a result of the procedure that's bad is an adverse event.

            If you look at these numbers of retinal detachment, cataract lens haptic dislocation, power calculation errors, inflammatory response, lenses explanted, lenses exchanged, lenses reattachment and surgical trauma, the numbers are much higher. 

            It's about a 3.9 percent incidence and I think that's per eye.  I'm not sure if it's per patient.  I really couldn't tell from looking at the data and I think it's really important to the consumer that they know the difference there because if they see it's per eye and they have two eyes, they may say, "Gee, is it twice that," whether we know or not the statistical validity of that assumption.

            Patient symptoms.  Again, it's very nice that they segregated out for us those patients who preoperatively responded no and postoperatively responded yes.  This removes the confounding variables of glare problems that we know are prevalent in this highly myopic population.  It is very significant that in patients with pupils over 5.5 mm under mesopic conditions halos were reported in 23.8 percent.  These are very high numbers. 

            These are very high numbers because the sponsor took the time to segregate out the pre-op response being no and the post-op response being yes.  In many studies this has not been done so this is basically induced problems either from the procedure or the device or the surgical technique but they are induced problems.

            Pressure.  I have to defer to Dr. Coleman.  I'm not a glaucoma specialist.  Unfortunately I'm not good at even maybe defining it as Dr. Stulting alluded to those of us who are cornea surgeons, but I was very alarmed that gonioscopy was not performed in any of these patients preoperatively or postoperatively. 

            I am very concerned that in the darkly pigmented patient the role of pigment dispersion from this lens may be very high.  We just don't know yet but I find it hard to imagine that enclavation of the iris would not result in pigment release, flare, some level of chronic inflammation, and possible acceleration of cataract formation or glaucoma.

            The endothelial cell data was very difficult to analyze.  It's been adequately, I think, addressed by Dr. Gray, Dr. Mathers, and Dr. Schein.  I have very little new to add.  You all know that from baseline to three years the decrease was 4.7 percent but this loss seemed to be higher between the second and third year as compared to between the first and second year intimating that there is an increase in endothelial cell loss over time taking into account the lack of standardization of what we're looking at.

            Anterior chamber depth was addressed by Dr. Mathers.  There were only six eyes but in those eyes there was an alarmingly high rate of loss of endothelial cells alluding to the fact that the depth of the anterior chamber plays a big role in endothelial cell loss in these patients either from surgical trauma or ongoing trauma from eye rubbing or something of that sort.

            The number of eyes that demonstrated greater than 10 percent loss was analyzed and it was looked at.  I don't need to go on about this.  And a consistent cohort was also looked at showing 2.38 percent overall loss.  Just clearly the endothelial cell count has not stabilized in this short time period that we're looking at during this accelerated review.

            I don't know what the endothelial cell loss rate is but it's somewhere between 1.58 and 3 percent.  I think that 2,000 cells per millimeter-squared is way too low of a cutoff, especially in a 21-year-old. 

            In summary I'll tell you that I had a very hard time reviewing this PMA due to lack of standardization and enrollment criteria, outcomes reporting, lens characterization, adverse event definition, gonioscopy, and specular microscopy.  And though I'm not sure, I've chosen purposely not to answer the panel's questions during this presentation.           I would use this time to ask the Agency and sponsors who are in the development process of improving our field by creating these phakic IOLs that it's very difficult to give a fair and reasonable analysis of safety and efficacy without standardization of these key features.  Thank you.

            DR. WEISS:  Thank you very much.  I want to thank all of the reviewers for their excellent and clear presentations.  At this point we are going to go on to the panel discussion of this PMA.  I would ask FDA if they could come forward to the podium and then just present each question so that we can discuss it in order.

            While Dr. Lepri is doing that, the first question which I will just read out is, "Do the endothelial cell data presented in the overall analysis stratified by anterior chamber depth and the extrapolations over time provide reasonable assurance of safety in the ARTISAN myopia lens." 

            What I would like to do is just go around and get the opinions.  If you want to give me a yes or a no, that's the best opinion possible.  If you want to add some comments, that's okay as well.

            Dr. Schein, do you think that there is reasonable assurance of safety on the basis of the endothelial cell data, question No. 1?

            DR. SCHEIN:  No.

            DR. WEISS:  Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  No.

            DR. WEISS:  Dr. McMahon.

            DR. McMAHON:  No.

            DR. WEISS:  Dr. Bradley.

            DR. BRADLEY:  I think it's impossible to project out 30 years.  My answer is I don't know.

            DR. WEISS:  I don't know.  Okay.  Dr. Macsai.

            DR. MACSAI:  From the analysis of what I was given to review, I would have to say no.

            DR. WEISS:  Dr. Grimmett.

            DR. GRIMMETT:  In short, no.

            DR. WEISS:  Dr. Mathers.

            DR. MATHERS:  No, but I do think that the age of the patient when this is performed plays a role in that decision.

            DR. WEISS:  Dr. Casey.

            DR. CASEY:  No.

            DR. WEISS:  Dr. Coleman.

            DR. COLEMAN:  No.

            DR. WEISS:  Dr. Van Meter.

            DR. VAN METER:  No.  This may not be the time to discuss it but I think that it's reasonable to talk about whether or not we want to lump all surgical and operative issues in with the device itself because we ourselves have said that anterior chamber lenses for pseudophakic correction are not a legitimate comparison because of the differences in surgical technique.  These are sick eyes and they've had previous surgeons.

            DR. WEISS:  Actually, since we're not -- I just want to speak to the particular question so that may --

            DR. VAN METER:  No.

            DR. WEISS:  Dr. Smith.

            DR. SMITH:  No.

            DR. WEISS:  Dr. Huang.

            DR. HUANG:  I don't know.

            DR. WEISS:  Is there anyone that requires any discussion on this point?  I say this with great hesitancy.  Is there anyone who just requires some discussion?  Personally I think many of the points, if not all the points that are relevant, have already been elucidated.  Okay. 

            Dr. Lepri, do you need anymore information from the panel on Question No. 1?

            DR. LEPRI:  I would say no.  That was pretty clear cut to me.

            DR. WEISS:  We're trying.  Question No. 2.  I think this way of going around the table does work so we're going to try this another time.  Question No. 2.  "Do the other data, not the endothelial cell data but everything else, presented in the PMA provide reasonable assurance of safety?"

            Dr. Schein.

            DR. SCHEIN:  No.

            DR. WEISS:  Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  No, and I would just like to second Dr. Schein's concerns about having to take into account time under observation for incidence of events.

            DR. WEISS:  Actually, from my elucidation, I would -- you can contradict me if you like.  Would it be helpful to you if whoever -- if someone feels that the other data do not provide reasonable assurance safety, if they just specify what data they are concerned about?

            DR. LEPRI:  Exactly.  I was just going to mention that to you.  If you specify what in particular made you make that decision, it would be helpful to us.

            DR. WEISS:  So, Dr. Schein, you felt the other data do not provide reasonable assurance of safety.  Can you just elucidate what your particular concerns are?

            DR. SCHEIN:  Lens opacities, retinal detachment.  Need to move, reposition, or exchange the implant.

            DR. WEISS:  Are you concerned that there's a higher rate of retinal detachment with this lens than the normal patient?

            DR. SCHEIN:  The concern is that the procedure coupled with the device adds significant risk of retinal detachment compared to not having the procedure or device.

            DR. WEISS:  Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  Yes.  I would rely on the clinical expertise to specify where there's a concern.  Then I just felt like the incidence rates that we've been given are probably undercut because they are not presented in a Kaplan-Meier or taking into account time under observation.

            DR. WEISS:  So you had safety concerns because the statistics as they were presented didn't give you the information you wanted?

            DR. BANDEEN-ROCHE:  Yes, in combination with the clinical concerns expressed by my colleagues.

            DR. WEISS:  Okay.  Dr. McMahon.

            DR. McMAHON:  In the aggregate, no.  If you look at the complication or adverse event rate as compiled by Dr. Schein and Dr. Macsai, the incidence rate is too high.  If you start talking about individual rates, I have a hard time getting a handle around it to know whether that is too high individually or not.

            DR. WEISS:  So, from what I understand that you're saying, it's hard to answer this question because you don't have the numbers that you want.

            DR. McMAHON:  Correct.

            DR. WEISS:  What numbers would you want from sponsor?  What would you like to look at which would allow you to make that determination? 

            DR. McMAHON:  I think the time dependent issues that have already been raised are the ones that I would be looking for.

            DR. WEISS:  Dr. Schein.

            DR. SCHEIN:  And the parsing of events and complications from those with clinical significance separated from those without.

            DR. WEISS:  So basically put all the adverse events together and also put them in a format so that it's per patient and not per eye.

            DR. SCHEIN:  Or both.

            DR. WEISS:  Both.  Anything else in terms of the statistical?  Any other things that I have not mentioned that you would want?

            DR. SCHEIN:  No.  I think Dr. Bandeen-Roche emphasized we want the amount of time or timeline.

            DR. WEISS:  We want a timeline.  We want binocular.  We want monocular. 

            If you could just speak into the microphone so we can hear.  Could you just repeat that so we can make sure we got it on the transcript.

            DR. SCHEIN:  I don't know how far back to rewind. 

            DR. WEISS:  Tell us your wish list.

            DR. SCHEIN:  Yes.  I think most of it is in the presentation I gave a few moments ago but it's to look at adverse events as a group on an eye and patient basis, adverse event being defined as occurrences which have the potential to cause significant harm or loss of vision and have those separated from adverse events such as the need for punctual occlusion, for example, which I do not feel have major clinical significance to present each of them on a per-eye and per-patient basis, and in a time dependent fashion so that we can see whether the likelihood of these complications, either individually or cumulatively, is increasing with time or decreasing.

/           DR. WEISS:  This is more of a data question as opposed to being convinced that aside from endothelial cell data that there is a higher -- there is no assurance of safety.  In other words, if we had the data right here and you looked at it, you might have the possibility of saying that it's safe excluding questions on the endothelial cell data.

            DR. SCHEIN:  If we analyses on the entire cohort with a high or low-loss to follow-up at perhaps a three-year period, and they, indeed, showed a gradual decrement or lessening in adverse event rates, I would feel a lot better.

            DR. WEISS:  Dr. McMahon, did you have anything else to add?

            DR. McMAHON:  No.

            DR. WEISS:  Dr. Bradley.

            DR. BRADLEY:  I'm not sure.  I'm still listening.

            DR. WEISS:  Dr. Macsai.

            DR. MACSAI:  Well, I think Dr. Schein has very nicely summarized the issues for safety.  But I also -- maybe this is speaking to efficacy but since the sponsor put outcomes of vision as part of safety, I would like to see the data stratified by lens power.  We only saw it for Group AB and I would like to see it for everyone else.  I guess I would like to see everyone all together all the time, not all these groupings.

            DR. WEISS:  So what I'm continuing to hear from members of the panel, again, aside from endothelial cell data, is the need for reprocessing the data looking at another way more information in order to make a determination of whether it is safe or not.

            DR. McMAHON:  Marian, are you looking for preoperative MSRE or do you think there is something specific relative to the implantable lens?  They are going to be linked but --

            DR. MACSAI:  I'm not sure but when we looked at the stratified data that we got the day before the package was sent out to the primary reviewers and if you use 50 percent of eyes targeted for emmetropia being half diopter, that was not achieved at the -6, -7, -15, and -16 diopter groups of implants and the same for 75 percent being within + or -1 diopter was not achieved for the 13 and 15 diopter group. 

            In these specific stratified groups I don't know why that's the case.  I don't know if it's a safety issue, an efficacy issue.  I need to know more about that.  That's only in groups AB.  I don't know about the rest of the patients.

            DR. WEISS:  Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  I guess I would just like to remind everyone of a double-edge sword.  Certainly the subset analyses are very interesting to look at but there's low precision and low power for many of these analyses so they have to be taken with a grain of salt, particularly statements such that there is no statistically significant different by age.  For instance, a statement like that the power may be so low that there really is very little evidence underlying such a statement.

            DR. WEISS:  Dr. Grimmett.

            DR. GRIMMETT:  This is Dr. Grimmett.  I'm just transcribing here.

            DR. WEISS:  And doing it well.

            DR. GRIMMETT:  Thank you.  Regarding the second question, I'm uncertain to provide an answer to that right now.

            DR. WEISS:  Dr. Mathers.

            DR. MATHERS:  I'm also concerned about the development of two things, cataract and retinal detachment.  I think that the absence of a good control group makes a cataract assessment extremely difficult. 

            Recognizing that cataract exist in a higher percent of these people, I would still like to have a better handle on this because the chronic perhaps low-grade inflammation and other issues will most likely, as we have some indication here, lead to accelerated cataract which has implications for retinal detachment because this group of high myopes do not do cataract surgery well and that risk them for retinal detachment. 

            I am concerned about particularly those two safety issues.  I agree with the other comments that it's difficult to be certain about the other safety issues.

            DR. WEISS:  Dr. Casey.

            DR. CASEY:  I'm not sure either.  One of the things I was concerned about is the fact that, again, as I mentioned earlier, there was not a lot of data that was presented on patients who might have irises that might be thicker, might have greater pigment dispersion, particularly minority patients. 

            While a lot of these patients -- well, we're saying that the age with which these lenses can be inserted can start very young, certainly a lot of patients who are in minority groups may not have other diagnoses at, say, 20 or 30 but the rate of diabetes, particularly in patient populations that I see, is significantly greater in those patients that didn't have more pigment dispersion.  Pigment dispersion is a big problem for me and its relationship possibly to glaucoma.  I'm concerned about that as well.

            DR. WEISS:  Dr. Coleman.

            DR. COLEMAN:  I'm also concerned about glaucoma as Dr. Casey and Dr. Macsai have pointed out.  One of the things I'm concerned about is about the subjects were on medications long-term according to the sponsors.  The issue is that this is probably just for elevated intraocular pressure because if they are not looking at the nerves and not doing visual fields, you don't know if they really do have glaucoma so this is really a pressure related treatment. 

            One of the issues is that with high myopes you do have an increased risk for glaucoma and so there could actually be a lot of undiagnosed glaucoma that may or may not have gotten worse by the placement of this lens and we really don't know that.

            One of the issues, too, is that for those 10 individuals that are on long-term medications for the high eye pressures, you really don't know what's going on in the angle because gonioscopy was not done so you don't know if they have peripheral anterior synechiae or exactly why are they having this long-term elevation of their intraocular pressure.  Is it part of the natural history or not.

            In addition, they mentioned that they didn't have pupillary block in the information for the clinicians.  However, there was a case of pupillary block they thought might have had to be reversed by iridotomy so it does look like there are some issues with pupillary block and I'm quite concerned about the glaucoma issues.

            DR. WEISS:  Dr. Van Meter.

            DR. VAN METER:  I think some of the data that we have looks like a little more longitudinal follow-up would help also.  For instance, from the concerns we've discussed, in patients that have 8 diopters of myopia or less, meaning the lower groups, we have 33 patients only entered into the study and only 16 of those patients are out t three years so that's not really enough information.  It would be nice to follow them long enough to get more people in the group.

            Likewise with your concern about brown iris patients, there were 297 patients that had brown irides entered into the study.  We only have information on '98 of those.  On those patients that have 8 diopters -- well, I mentioned 8 diopters or less of high myopia. 

            In the younger patients, 35 or younger, it looks like there are 94 patients entered into the study.  We only have information on 23 of those.  A little bit more follow-up data on the cohort of patients that we have I think would also help.

            DR. WEISS:  Dr. Smith.

            DR. SMITH:  At the present time I don't think the data presented provide reasonable assurance of safety for the reasons related by my colleagues, the first of which is I can't find a single number to attribute for all adverse events added together per patient. 

            Also roughly about half of the patients enrolled in the study are still ongoing.  I think there is longitudinal data that can come about in the future that would provide additional information that is required.

            DR. WEISS:  Dr. Huang.

            DR. HUANG:  I guess I'm a contrarian to the group.  I do think that current data have provide enough safety assurance because we really don't have a safety guideline from the FDA or from the ophthalmic community.  I think the high myopic group is very difficult to study.  These patients intrinsically have a high risk of glaucoma, high risk of cataract, high risk of retina detachment. 

            Many of the questions I think is important such as endothelial count and such as another potential and longevity of the visual acuity and the patient's associated complication but I think those can be performed in the post-market surveillance.  I really don't think we should continue to wear on submitting more data. 

            Our panel member mentioned that more of the stratification sometimes gives you more confusing data.  You review the scientific data more on stratification.  You have a smaller number subset of the patient and the validity of the instrumentation become much less.  Thank you.

            DR. WEISS:  Actually, I'm glad you had a contrary opinion because I would like to -- I hear sort of a consensus -- I'll just make my comment and then get to Dr. Mathers -- hear a consensus of the interest of either more data or reevaluating the data we have.  That doesn't necessarily speak to the device is not safe.  It's just that can we get some more information in order to determine if it's safe or not.

            Now, the way that we can do that is with premarket or post-market.  You brought that up and what I would like to do after we have Bill make his comment is have the panel discuss what additional -- would this be helped or would your concerns be helped if we had more of the information from three years, if we had people followed out at a longer time point what would you need in order to determine if this was safe.              I'm going to open that up to actually the first two questions, not only all of the data, the endothelial cell, the lens data on retinal detachment, etc.  What do you need to make a determination?  Dr. Mathers first, however.

            DR. MATHERS:  We're asked to make an assessment here which is sort of a global assessment about safety and that's what we've done.  I think it can be seen in another context.  This is a difficult patient population. 

            They are requesting permission to do this in a wide range of ages and myopic correction but we are trying to address a need that is very real and safety in this sense can be seen as a relative safety versus the degree of, shall we say, disease that we are trying to deal with. 

            I think if you narrow the window you will come up with the population for which at least some of us would think this wasn't such an unsafe alternative.  For instance, a high endothelial cell count, a patient who is relatively older but not perhaps fully into the cataract range because that then just leads them to cataract surgery, and a high myopia. 

            These patients have very little alternatives and this device considering other issues might be more reasonable for them.  I think it's not for the wider group but a 45-year-old with a 2,800 count and a -15 is a different patient.

            DR. HUANG:  I do agree. I think either modification of the approved indication or modification of the safety requirement is relevant.

            DR. WEISS:  And we are going to be getting to that in a while when we get to question 3 which is the proposed statement of indications as far as addressing the minimal refractive error and the minimal endothelial cell count which we can also associate with the age. 

            But on this particular issue with safety, does anyone have any comments in terms of aside from reprocessing the data that we already have bringing it out at a longer time point?  Is there anyone who feels that would answer their concerns or is that not necessary?

            Dr. McMahon.

            DR. McMAHON:  I don't know if we can answer that question.  I think it's on sponsor's behalf to provide data that would in the case of endothelial cell loss, for example, which we are focusing on, they need to provide data that would be assuring to us. 

            If that can be done with analysis of data that already exist, which I think they would have already presented if that was the case, in terms of completing the analysis of patients that they have enrolled, that might be enough.  If that is the case, yahoo.  And if it's not, then I think they need to follow them longer until they can demonstrate a flattening of that slope in my view.

            DR. WEISS:  Dr. Grimmett.

            DR. GRIMMETT:  Michael Grimmett.  I answered the second one that I'm not certain and I certainly agree with Dr. Schein and Dr. Bandeen-Roche that having some life table analysis would be very helpful regarding these other complications.  Looking at the application in general, I wasn't overly alarmed about the other safety features irrespective of the endothelial cell loss data. 

            I don't think necessarily that it's way out of line.  I agree with Dr. Mathers that with specific entry criteria including endothelial cell cut-off data and age taking into account high myopes where there are other options in the market place.  I think I could be convinced that it may be a calculated risk but one that those patients may be able to take.  That is how I feel about the second part of the data.

            DR. WEISS:  Dr. Van Meter.

            DR. VAN METER:  I also think that when we're talking a about safety it is necessary to separate out surgical position dependent variables from that of the device itself.  As I almost said earlier, having a wound leak is not really a process of the device itself.  That's a surgeon specific variable.  Many of the problems that we have with anterior chamber lenses have to do with surgeon variables and not the piece of plastic that we're putting in the eye. 

            The other point I want to emphasize is that if you eliminate those myopes that are less than 8 diopters for which we have little data, those 8 diopters and the patients with 9 diopters and higher correction really don't have other good alternatives for them.  This device fulfills a niche.  Like cataract surgery, there is really no other alternative for these patients.

            DR. WEISS:  So what I'm beginning to hear is that even though there seem to be somewhat of a consensus that the endothelial cell data did not provide reasonable assurance of safety that you could get around this by having stipulations of minimal endothelial cell count per age so that you could project out at a certain point to try to ensure a certain number of endothelial cell counts when they were elderly if we were using a linear model to do this.

            DR. VAN METER:  Van Meter.  If I may add to that, for instance, if you're looking at a 25-year-old that has a cell count of 2,000, even though that is an acceptable cell count, that is not a normal endothelium for a 25-year-old.  For someone that age you may want 2,800.

            DR. WEISS:  If there was consensus that this might be a way to go about things to balance the risk and the safety, in that setting would there be -- do any members of the panel feel it would be helpful to have a post market or a premarket study in conjunction with that amount of guidance or that's unnecessary? 

            Dr. Schein.

            DR. SCHEIN:  The question -- this is Oliver Schein.  The questions that Dr. Weiss is currently raising, there is more than one issue simultaneously.  One question I think you're asking is is it simply a matter of reanalyzing the existing data to meet my or other individual safety concerns. 

            To that I would say that's a precursor, a prelude for what needs to be done because we then want to look and see what the analyses look like once they were done.  Secondly, would I feel that data showed adequate safety when we have on the order of 60 percent of patients or eyes meeting two years and 30 percent meeting three years no matter what it showed.              I think that is a second issue.  We may differ on that around the table.  I would like to see much more than 60 percent of two years.  I understand that the directions or the mandate may have changed in midstream to make it harder to get more data at three years or, at least, to get as much as we would otherwise anticipate. 

            Those are two separate issues.  It's hard to predict if one saw the data what one would then make of it in the absence of seeing the data.  Now, if analysis of the data which included more extensive follow-up at two to three years showed reasonable safety, you know that I would feel very strongly that we still needed a post-market surveillance study. 

            That is predictable over here, I know.  The issues there are very different because in that setting you want a large sample of patients where you're only interested in the most severe complications.  Off the top of my head I would look at explantation, corneal transplantation, retinal detachment.  You might think of one or two others but in a very large sample over a several-year period.

            DR. WEISS:  Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  First, I would just like to second Dr. Schein's thoughts on 60 percent at two years being something that I'm not at all comfortable with.  I would like to see a much more complete follow-up than that.  And the need for a post-market surveillance study. 

            The other thought involves the extrapolation issue.  In other words, can we pick an age and a severity at which we are comfortable approving the device.  It just seems to me that it's very complicated and the few issues I would like to raise are, first of all, the measurement of the endothelial cell count.  We've heard how variable that is.  When we determine a threshold at which a patient is eligible to have this device, that variability is still there and has to be considered in terms of their measurement for eligibility. 

            The second is just to reiterate the point that it's not the mean projectory that is really the most important thing but estimating some percentage who are really at elevated risk. 

            I would just briefly say that I think the analysis that Dr. Gray presented, I really can't think of a better way in light of these data to try to estimate those percentiles other than to maybe also look at the random effects distribution itself and not just the -- the estimated distribution and not just the posterior estimates. 

            And then finally there's the issues of cataract induction and what happens when people then go to have cataract surgery at an older age.  I don't have a magic answer but it just seems complicated.

            DR. WEISS:  From what I hear, and I could use Dr. Rosenthal's input at this point, there are two lines of thinking.  One is that there are safety concerns but these are going to be overweighed by the efficacy that has been shown and some of these safety concerns perhaps could be worked out by Agency with request for further data which are already present.

            The other mode of thought that I'm hearing is that the safety concerns are such that in order to make any further determination on this device the further information about the data must be forthcoming and this would hold everything else up because you don't know if the efficacy would be outweighed by these issues because you don't have the data yet.

            Ralph, do you have any input as far as any

-- that's just two modes of thought and that's how you can think.

            Dr. Van Meter.

            DR. VAN METER:  I was just going to add that some of the problems can be overcome with the appropriate labeling and informed consent which is another issue that would overshadow both of these two arms you've mentioned.

            DR. WEISS:  Well, I think there's one mode of thought of that, Woody, but I don't think that Dr. Schein and Dr. Bandeen-Roche would feel that labeling would address their concerns.  Am I correct?

            DR. SCHEIN:  You're right because there's an assumption that it has been found safe and effective and here are some labeling issues.  There is a contradiction there.

            DR. WEISS:  Any other comments on this?  Dr. Coleman.

            DR. COLEMAN:  I was going to say that I'd be interested in gonioscopy even though it has not been done preoperatively the could do it at this point and follow up and that way they could actually look at the amount of pigmentation and the angle would also address some of the concerns that Dr. Casey brought up. 

            If there are PAS they would have to then attribute it to the device instead of not knowing whether it was pre-op or not.  We could also indicate in the labeling that there was such a small number of minority participants you could not really -- we don't have the information in this group.

            Dr. Mathers.

            DR. MATHERS:  I think that the endothelial cell data and its extrapolations get very complicated and iffy and there are lots of problems.  But Dr. Gray's single summary statement that 38 percent of the subjects would have a risk to have a two percent loss which is a 50 percent reduction in 25 years. 

            If we use that as a guideline and figure who could tolerate a 50 percent loss compared with their current circumstances of their disease, we might be able to assign a category of patient but that would fit given reasonable labeling. 

            It clearly wouldn't fit a 20-year-old but you could ascribe an endothelial count and age and myopic degree which would fit that relative loss rate.  At least consider this because I know that there are patients who would like to have this who could have a relative level of risk.

            DR. WEISS:  I'll just add one comment on that and then Donna Lochner was going to make a comment.  I think if you did that, then you would also have to add labeling addressing Dr. Schein's concern that basically you would be saying this is safe and effective but that we do not know the safety X number of years down the line and we do not know the risk of endothelial decompensation and corneal edema, etc., which is why you are suggesting putting a template in there to try to minimize the risk.  If we do find out that this does have a continued cell loss or increased cell loss, then we expect it.

            Donna.

            MS. LOCHNER:  I just wanted to make a comment about the point with respect to percent accountability.  That is one of the things we look at when a PMA first comes in, the accountability, and we want to see that we're not seeing high loss to follow-up rate which may be biasing the data for the subset of data that we're looking at, the primary analysis.

            The company enrolled a large number of subjects.  The guidance from the FDA and the panel in the past has been that we need at least 300 after visits to appropriately power the kind of safety endpoints we're looking for.

            So I think just the fact that they, first of all, reached 300 was favorable was favorable to FDA in terms of powering the study for these low-level complications.  Then, I think, you have to look at accountability separate and look more at was there loss to follow-up within that group that reached the 300, the people that were eligible for that visit.             Was there a high loss to follow-up rate, not what is the overall percent accountability of the subject so the fact that they have 60 percent accounted for at a visit isn't necessarily a concern in this instance since they reached adequate sample size to power for the kind of complications we were looking for.

            So I just want to make that clarification.  I may or may not have been totally clear as you look at just the overall numbers that you're getting data on at a particular postoperative visit versus how many were enrolled from the start and whether they were eligible for that visit.

            DR. WEISS:  Dr. Macsai.  Then we'll just continue along the table.  Dr. McMahon, then Dr. Schein.  Then I think we're going to be wrapping this up after those three comments, these particular two questions.  But I will want to after these three comments sort of have a poll in terms of what the consensus is at this moment in time as far as the safety issue goes.

            Dr. Macsai.

            DR. MACSAI:  I wanted to make two comments and one is in regards to Donna Lochner's comment about adequate numbers of 300.  If 300 eyes is enough to get this expedited review, then I would expect on those 300 eyes data that is analyzable.  If it takes 600 eyes to get 300 eyes of data that's analyzable to establish safety, then that is what I personally may feel is required in order to answer the question is it safe and is it effective.  I guess I was not clear how we got to this expedited review state.       

            MS. LOCHNER:  But the numbers don't factor into the expedited.  I think you really have to separate the expedited issue from the numbers.  When I say 300, that is 300 analyzable.  That is 300 people who have had follow-up in these kind of studies at the one-year visit, at the two-year visit, at the three-year visit.  These are the primary analysis points.

            When you get to 300 that have those data, you have a certain extra number that you needed to get there and the loss to follow-up within that group has to be reasonable.  A 10 percent figure is usual.  It doesn't mean, though, you can apply that to the total number enrolled and that may still be active. 

            That's my point I'm trying to make.  The company should not be sort of penalized because these people are active.  When they've reached a sample size that we have given guidance, the panel has given guidance, would be sufficient to power these kind of complications.

            Dr. Rosenthal, did you have a comment on this?

            DR. ROSENTHAL:  I was just going to say I think we have to be on a level playing field and the original panel input was that in order to power the safety issue, one had to have 300 eyes.  If you now feel that in this instance 300 eyes was not satisfactory and you need more to power the safety issue, that's a reasonable request.  But if you need another 300 eyes just to make that accountability table with 90 percent, it would be not a level playing field for the other companies we deal with.

            MS. LOCHNER:  I understand now what you were talking about.  I guess my comment would be that I'm not convinced.  I don't know that it's actually 300 that is required but I'm not convinced that we have enough longitudinal data on the safety issue of endothelial cell loss rate in this group that we analyzed for today.  That would be comment No. 1.

            Comment No. 2 about the pigment dispersion and the comment that Dr. Weiss made about labeling I would actually disagree with.  I think that this sponsor has enrolled compared to other levels of enrolling 13 percent minority population, 6 percent Asian, 3 percent Black, 4 percent Hispanic. 

            Although that in no way represents the population of the United States, that's much higher than we normally see in these kinds of analyses so it would be really important to look at those patients.  I don't think that should be included in the labeling in anyway saying that it wasn't looked at in minority populations because, in fact, it was.

            DR. ROSENTHAL:  So I'm gathering that you would like a reanalysis of existing data on the cohort that has come through for two and three years.

            DR. MACSAI:  Yes.

            DR. ROSENTHAL:  Or that you feel in order to get more data for analysis on the minority patients, we need to get to three years so that sufficient number of patients are accumulated.

            DR. MACSAI:  I don't know the answer to that.

            DR. ROSENTHAL:  I don't either.

            DR. MACSAI:  So I don't know.

            DR. ROSENTHAL:  But if you feel that minority -- if the panel feels that it's important to comment on minority data, that is certainly something we can ask of the sponsor to provide us with that data and if they don't have it out to an appropriate time, we can certainly ask them to do so.

            DR. WEISS:  I think the comment I was making based on Dr. Casey's comment was in terms of the pigment dispersion that you need to look at this category of people to find out if they are having a different rate of problems.  My assumption was the data wasn't there but you are 100 percent right.  Maybe it's that the data hasn't been looked at.

            Now, I know you don't know the answer to this question but I'm going to ask you anyway.  Not knowing the answers to things hasn't stopped us even at this point so we can still discuss it.  Do you want data going out at a longer time point either premarket or post-market?

            DR. MACSAI:  Yes.

            DR. WEISS:  And what would you want?

            DR. MACSAI:  Me?

            DR. WEISS:  You.

            DR. MACSAI:  I would want data going out at a longer time period looking at --

            DR. WEISS:  What time period?  Not the details of it but would you want further premarket in terms of going out to four years or post-market?

            DR. MACSAI:  Well, Dr. Gray said four to five years and so I don't know if he meant four or five or 4.5.  I don't know what but he said four to five years might help.  Then, again, we have to do kind of like blind extrapolation on mushy data so I don't know.  When we were talking about the pigment dispersion, I can't tell you if those darker pigmented patients and darker irides need to go out further because we haven't looked at them.

            DR. WEISS:  I think what Dr. Gray was saying is even if we brought out four or five years it wouldn't help us to project to 20 years. 

            DR. MACSAI:  Dr. Gray, can you clarify?

            DR. WEISS:  Dr. Gray will tell us exactly what he said.

            DR. GRAY:  Let me just clarify what I think I might have said.  If you are trying to distinguish between a linear and a nonlinear function, then I think we need a lot more time to make that distinction.

            DR. WEISS:  Can you quantify a lot more time?

            DR. GRAY:  Like 10 years.

            DR. WEISS:  Okay.

            DR. GRAY:  That's just a guess.

            DR. WEISS:  Ten additional years?

            DR. GRAY:  Out 10 years maybe but you need a longer term follow-up.  When you're feeling a regression and you are trying to -- more years matter more than more patients so every time you add on an extra year at the end, it really helps.  It's like holding a stick at one end and trying to poke at something with the other end. 

            You don't have a lot of leverage.  If you grab toward the middle more, it's like having more years in your regression and the variability will go down a lot.  Every time you add on a year or so, it makes a pretty big difference in terms of the  variability you'll get at the end.

            DR. WEISS:  Okay.  So every little bit helps.  Dr. McMahon, did you have a comment?  Then Dr. Roche and then Dr. Schein.

            DR. McMAHON:  I imagine 30 years ago the panel when they are dealing with the first IOLs on the market had a very similar conversation not knowing what the future was.  The way around that at that point was, "We'll let you implant these lenses in 75-year-olds or 65-year-olds and let them go for a while and if they fall apart, then we know we made the wrong decision.

            And that is because the need was great, the need for high myopes is great as well, as Dr. Mathers pointed out.  We have a problem, though, in that the cap here is that there is potential cataractogenesis component of this.  In the practical use of saying, "Let's implant this in 70-year-old and let you go for another five years and reassess," doesn't seem very practical.

            At the same time we're bordered by the fact of not being able to adequately extrapolate with any high degree of assurance and endothelial cell dropout over a period of time so we're in a catch 22.  Out ultimate obligation is to our patients and I think if this is going to be approvable, I think we need to be highly conservative and pick an older age group with a high density count in a select group of higher myopes that really would benefit from this. 

            The notion of doing this at 5 diopter myopes right now, I think, is ludicrous.  I think the notion of doing this in 20-year-olds is absurd.  I think the point is do you pick and where do you pick.

            If we are going to think in terms of approvable versus nonapprovable, which in my view, the panel should kind of make a decision right now because if it's not approvable at this point in the majority, I don't think we need to have any further discussion unless the Agency really needs to know more.  The other is if it is approvable with conditions, the notion is how restrictive are those going to be?

            DR. WEISS:  Then the Agency needs to know more.

            DR. ROSENTHAL:  May I just comment?

            DR. WEISS:  Yes, Dr. Rosenthal.

            DR. ROSENTHAL:  Approvable with conditions we need the conditions.  Not approvable we need to know what is necessary for the company -- what issues are necessary for the company to deal with in order to put it into an approvable package understood that we carried the direction -- the discussion in two different directions based upon that.

            DR. WEISS:  That's why we're going to reach a little bit of consensus after this one to see which way we're going.

            Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  On the point of the 60 percent at two years it's not a power issue.  The concern is that those are perhaps systematically different than the subsequent 40 percent.  I don't have a good sense for in this case whether that is likely or not. 

            In terms of the endothelial cell count, I've been sitting here thinking a lot about something we've discussed before which is the issue of flattening out.  From the discussion going around the table today, it seems there hasn't been nearly as much discussion about it. 

            I don't know whether the clinicians are comfortable if, in fact, the rate of decline is linear or if safety could only be demonstrated by flattening out.  And then, Dr. Gray, I guess I would ask if -- I suppose if the rate were just about to flatten out then another three years of data might at least give a reasonable indication.  I don't know but maybe not 10.

            DR. WEISS:  Dr. Schein.

            DR. SCHEIN:  The issue has been addressed.

            DR. WEISS:  Dr. Bradley.

            DR. BRADLEY:  Yeah.  I think we've talked about the issue of endothelial cell count a lot and I'm trying to put it into some terms that would allow us to come to a decision.  I think Dr. Mathers and Dr. Huang raised the obvious point that those patients with high-cell density and those who are older are at less risk. 

            I think the obvious implication is that by changing the guidelines for what patients are eligible for this procedure, we might be able to reduce the risk.  The question is how do we do that.  I think Dr. Stulting gave us a little diagram which captured the essence of how one would proceed. 

            The question is where are those lines drawn and based upon what data do we draw those lines?  In the end if we are going to approve this product for a restricted group of patients, we have to come up with some numbers.  It seems to me that is a very hard number to generate. 

            I wondered if maybe Dr. Gray might be in the best position of anybody to answer that.  But it seems to me if we are going say this procedure appears to have risk rather than set a cell count today, maybe we could give FDA guidance on what risk we are willing to tolerate, what percentage of patients we are willing to have experience this risk, the risk being ECC dropping to some criterion level.

            DR. WEISS:  Dr. Rosenthal.

            DR. ROSENTHAL:  May I just comment?  I actually think the Agency -- you may not believe it but I think the Agency can probably come up with a reasonable table based upon your input and you don't have to actually do it cell by cell while you sit here, and year by year.

            DR. WEISS:  Ralph, just for my edification, if we gave you a minimum age and how many cells we would like someone to end their life with, would that be sufficient?

            DR. ROSENTHAL:  No.

            DR. WEISS:  What do you need from us to come up with it?

            DR. ROSENTHAL:  Actuarial.  Yeah, I think anything you would like -- any input you would like to give we can put into an equation and hopefully come up with an answer.

            DR. WEISS:  So you could start out with --

            DR. ROSENTHAL:  I would like age.  I mean, we would obviously like what should end up after a certain period of time.  It's a gestalt, isn't it?  It's not the easiest thing but if that's the way you want to go rather than have you do it here, I think we could possibly do it for you.  That's all I'm saying.  I'm not saying that's the way you should go.

            DR. WEISS:  Dr. Mathers.

            DR. MATHERS:  Clinicians make a similar kind of assessment all the time in dealing with patients, a relative risk based on the patient's individual circumstances.  It may be a little more difficult here but I'm certainly willing to take a shot at it.  Given that, if you set the age too high, the patients don't need this because they've all got cataracts.  Then they undergo a higher risk for cataract because the endothelial cell loss in cataract is higher than this.

            DR. WEISS:  I would add that you are starting with someone who has a visual decrease that is corrected where these people do not.

            DR. MATHERS:  That's right, but it plays a role here.

            DR. WEISS:  Yeah.

            DR. MATHERS:  Because the cataract surgery fixes the myopia, they are induced to have that procedure even if they don't have a cataract.  I would say over 40, high myope nine or higher and an endothelial cell count of 2,500 would give you a window of 10 to 15 years of patient age where they are going to be okay for 30 years or so and when you are 40 to 50 years old and you are projecting 30 years downstream, that's not way out of line.

            DR. WEISS:  It seems to me, though, you're taking the -- you're targeting the presbyope myope to get rid of their myopia and would you not want to give the nonpresbyope the benefit of the fact that the lens is going to still be able to have some accommodation.

            DR. MATHERS:  But with 38 percent of the population that's going to get this, having a 50 percent reduction in 25 years, that's a great reduction so if you go down too far --

            DR. WEISS:  The problem is we don't know what their reduction.

            DR. MATHERS:  I know.  That's an assumption based on our best available data.  Of course, we would like guidance from Dr. Gray about that.  When we're considering that we care about the means but we actually care about the outliers even more, we have to draw a conservative view here and go on a higher rate.  That's my opinion.

            DR. WEISS:  Forty.

            DR. MATHERS:  Forty.

            DR. WEISS:  So, Ralph, I can see after some optimism on how this meeting was moving along we can easily get bogged down in an age, in an endothelial cell count, or whatever, but is this the route that you would like us to take in terms of discussing it?

            DR. ROSENTHAL:  Yes, in general.  I think based upon some generalities if you feel the device is acceptable, approvable, we will work on those lines to come up with some answers.  We may be coming back to you or individually with questions.  

            DR. WEISS:  We're going to have Dr. Grimmett, Dr. Macsai, Dr. Schein, and then Dr. Van Meter.

            DR. GRIMMETT:  Michael Grimmett.  That first question we answered was do the data provide a reasonable assurance of safety.  Around the table we heard no, a couple of uncertains, but generally it was no.  There are two ways to interpret that the way I'm looking at it.  One is we think it's unsafe.  Or option B, the data was not sufficient to tell us it was safe, the positive affirmation of safety. 

            I'm troubled with if the conclusion is truly it's unsafe, if we believe that is the case, then approving it for over 2,500 cells greater than 9 diopters at a certain age, we are allowing a patient to consent to an unsafe procedure simply because there's no other alternatives.  I don't agree with that. 

            I think that if we believe that it's not safe, then we need to have sufficient data to prove that it is reasonably safe.  I just want to clarify with the panel by voting no on that first question we're thinking it's unsafe or we're not sure that it is safe?  What did we think?

            DR. WEISS:  Dr. Macsai.

            DR. MACSAI:  You want me to answer Dr. Grimmett's question, Dr. Weiss?  Is that the question?

            DR. WEISS:  I guess Dr. Grimmett would like you to answer his question.

            DR. MACSAI:  Well, my answer to Dr. Grimmett's question would be, based on the data that I was given to evaluate, I would say not safe.  Not approvable based on the endothelial cell data.

            DR. WEISS:  I would actually want -- I'm going to narrow your question.  When we talk about endothelial cell count going down, is it not safe because your count is dropping or is it really only unsafe if you get to the critical point which we, unfortunately, can't determine here that your cell count causes corneal edema?  Which one of those is it?

            DR. MACSAI:  It's the same.

            DR. WEISS:  I think one of them we don't have the answer to.  One of them we don't have the answer to.  It looks like we know your cell count drops off for a period of time but what Dr. Mathers and Dr. Huang, I think, were suggesting is that if we suppose it's 1.7, 1.8 percent per year for 20, 30, 40 years, if you're going by that, how can we make it so that your corneal function will still be good enough so that even if you have a lower endothelial cell count it won't have any -- it won't have the same import as the concern that many people have raised here of the fiasco with the old anterior chamber IOLs.        If there is some way not to guarantee but to give you a better chance that you'll have the critical number of endothelial cells.  Because, of course, with this sort of device, we will never be able to prove it's safe unless we review this in 20, 30 years which is also not reasonable.

            DR. MACSAI:  Are you asking me?

            DR. WEISS:  I guess so.

            DR. MACSAI:  Then I would say to you if is the $10 million question here.  If it's 1.8 or if it's 1.9.  That if is based on nonstandardized data and I have personal concerns about making an if on something that I couldn't scientifically validate or analyze.           An if that is going to go out into the general public, not into the creme de la creme surgical hands, be used on patients who have alternatives for vision.  I've said this before at this table, people aren't dying out there from myopia.  It's not AIDS.

            DR. WEISS:  Dr. Rosenthal, do you have a comment?

            DR. ROSENTHAL:  You can deal with some of these issues by putting contraindications in the labeling and making the issue a liability for the surgeon himself.  That's just an option.  We've done that before, as you well know.

            DR. WEISS:  The medical community would be glad to hear about it.

            DR. GRIMMETT:  Can you define that a little better? 

            DR. ROSENTHAL:  You can say contraindicated under the age of such and such.  Would a surgeon go to the trouble of putting it in somebody under that age with FDA labeling saying it's contraindicated?  They can do it as a practice of medicine. 

            They can use any device that's on the market in anybody they want at anytime as a practice of medicine.  You know that.  And for not even the indication.  But would they if you put certain warnings and contraindications in labeling?  I don't know the answer to that.

            DR. WEISS:  Dr. Schein.

            DR. ROSENTHAL:  I thought no but maybe I'm wrong.  Oliver?

            DR. SCHEIN:  Well, I have hesitation in taking the extrapolated data with all its problems and then doing what Bill Mathers wants to do.  I feel it's what the clinician would do, as you say, once something is approved but there are so many ifs in the extrapolation that to then for us to go beyond that and subjectively put in age limits and endothelial count limits and so forth, I think, is really adding uncertainty to uncertainty. 

            I, frankly, feel that when it comes to endothelial cell counts, there is nothing that the sponsor can do with its current data set to give many of us the long-term assurance we need.  That's why I have come back to focusing on these other adverse events which I think are measurable and we can get from further two and three-year data. 

            Now, what could the sponsor bring to the table regarding endothelial cell counts that we haven't seen that might make me change my mind?  Well, if there are cohorts of patients in Europe or Canada that are five and 10 years out, even if we don't have preoperative endothelial cell counts, one could easily get endothelial cell counts on this group and then an age match control that didn't have an implant put in.            That would, at least, detect large differences that you might ascribe.  I think there are things that can be done to address that but there is nothing that they can do with existing data in three years that will make more precise the 30-year data.

            DR. WEISS:  I would like to just have two more comments and then we're going to have a straw poll on this issue.  Dr. Bradley and then Dr. Van Meter.

            DR. BRADLEY:  Just a couple of points.  If we take Dr. Schein literally and decide that we really can't make anything of these endothelial cell count data in terms of predicting safety, then it seems to me that we should never ever request these data again because if we cannot use them, they are really a waste of time. 

            I think, although in difference to Dr. Schein, implicitly around the table everybody is inferring the future from these data.  In fact, we are of the belief, although implicit, that, in fact, we can predict the future from these data.  That's why we collect these data and that's why we are here discussing them right now.  I have a feeling although on strict statistical grounds you're right.  We simply can't predict the future from them.  We are doing it and we in some ways are obliged to do that.

            Second point I would like to make is that if we set the criteria for who may or may not obtain this procedure based upon the likelihood that they will during their lifetime suffer a dangerously low level of endothelial cells based upon the data that we have now, it seems that it would be in the sponsor's self-interest to collect longer-term follow-up data to try and see if the curve, in fact, flattens out and then these probabilities will start to change. 

            In fact, the curve that Dr. Stulting presented to us would start to lower or change shape and the number of patients who could be safely included might expand. 

            Of course, the converse could happen and we might find the number of patients who could be safely included -- safely employ the procedure might decrease with those data but it would be incumbent upon the sponsor to collect those data to try to give us better predictability and potentially expand the range of patients who could safely use the procedure.

            DR. WEISS:  Dr. Van Meter.

            DR. VAN METER:  We know the rick of endothelial cell loss cannot be determined from the technology that we have.  I think the risk of cataract formation is fuzzy from the data that we have, but we do know the surgical skill affects both.  The surgical procedure of implanting the lens is probably more the variable than the lens itself is.

            I wrote down the same numbers that Dr. Mathers did, incidentally, before I heard his.  I think in the patients that are greater than 9 diopters myopic, patients have 2,500 cell count, and I use 30 instead of 40 because I think people that are 30 years old can make better decisions than patients that are 21.  Anectodally it seems like many of the refractive surgery problems that come from elective patients often are in younger patients rather than older patients just because of the processing.

            We should remember that there are not that many high myopes around so to ask the sponsor to gather a number of patients, I suspect they have thrown their nets fairly widely thus far to find the patients that we have.

            This is different than the -4 to -6 group.  I feel like with appropriate labeling there is a subset of the population who can be well served by this device and for whom the risks and the benefits are favorable.  I think that this would come with appropriate labeling.

            DR. WEISS:  So that's going to be the last word on this particular issue but what I did want to do is sort of have a poll at this point separating it into the two camps basically.  The one group believing that this is not safe and the other group with the thoughts that this is safe in certain situations which can be addressed in labeling and/or post-market studies and/or requests for analysis of the data -- reanalysis of the data that is already present. 

            So with that in mind, what I would like the panel to do is if you can raise your hands if you feel that this is not safe.  When I say not safe, I mean the issues cannot be address post-market. 

            They would have to be addressed premarket so you don't have enough data at this point to say that this is safe with the data that you have and you would not feel comfortable in addressing the issues with the stratification and labeling.

            DR. SCHEIN:  So the question is is the data we have to date does it demonstrate --

            DR. WEISS:  Safety.

            DR. SCHEIN:  -- on its own today does it adequately demonstrate safety.

            DR. WEISS:  To the level that you would not be -- maybe I'll rephrase it in the other direction because I think I'll have a better chance of getting a vote in the other direction. 

            Those of you who feel that the safety issues that are of concern can be addressed with stratification of endothelial cell count and age in the labeling and, in that case, if you got those put in the labeling, you would feel more confident about giving this your vote for reasonable safety, can you raise your hand?

            DR. VAN METER:  I'm confused.

            DR. WEISS:  You're confused.

            DR. VAN METER:  We're voting that it is?

            DR. WEISS:  We're saying it's safe enough.  It's not a vote.  This is just a poll.

            DR. VAN METER:  Straw poll.

            DR. WEISS:  A straw poll that it's safe enough that your concerns about safety could get addressed in labeling modifications.  Are you clear on that?

            DR. VAN METER:  Yes.  Thank you.

            DR. WEISS:  Okay.  Now can we have a poll of that again?  If you could raise your hands.  Dr. McMahon is that -- okay.  We have how many?

            MS. THORNTON:  Five.

            DR. WEISS:  Okay.  Those of you who did not raise your hands, what I would like is a vote how many of you feel that you need more premarket data to decide whether this is safe?

            DR. WEISS:  Dr. Rosenthal, and FDA, would that give you enough of a poll on those first two questions?  Are you satisfied with that?  Okay.  Seven to five that was.  It doesn't matter.  It's a poll and polls are polls. 

            FDA again.  This is the season for polls and we're in Washington and we know they can change.  The proposed statement of indications read, "The reduction or elimination of myopia in adults with myopia ranging from -5 to less than -20 with less than two degrees of astigmatism at the spectacle plane, patients with documented stability of refraction for the prior six months as demonstrated by spherical equivalent change of less than or equal to 0.5 diopters. 

            Does the panel recommend any modifications to the proposed statement of indications with respect to..."  There are three parts to this question.  (a) Minimal anterior chamber depth.  Anterior chamber depth of less than 3.2 mm were excluded in this study."  We are going to go around on this one.  We are going to start with Dr. Huang.  Do you think there should be any modification in the proposed statement that the minimal anterior chamber depth should be 3.2 or greater?

            DR. HUANG:  Yes.  Also proposed age limitation as well as the --

            DR. WEISS:  We're just going to answer that particular one and then we'll get into others.  Is that agreeable to you or you would like a different anterior chamber depth?

            DR. HUANG:  It's agreeable.

            DR. WEISS:  Dr. Smith.

            DR. SMITH:  Greater than 3.2 is agreeable.

            DR. WEISS:  I think right now it would read greater or equal to 3.2.  Am I correct?

            DR. LEPRI:  No.  I think it would be greater than 3.2.

            DR. WEISS:  Oh, just greater than 3.2.

            DR. LEPRI:  It was those that were 3.2 and less.

            DR. WEISS:  Okay.  Fine. 

            Dr. Coleman.

            DR. COLEMAN:  Greater than 3.2 is agreeable.

            DR. WEISS:  Dr. Casey.

            DR. CASEY:  I agree.

            DR. WEISS:  Dr. Mathers.

            DR. MATHERS:  Greater than 3.2.

            DR. WEISS:  Dr. Grimmett.

            DR. GRIMMETT:  Ditto, greater than 3.2.

            DR. WEISS:  Dr. Macsai.

            DR. MACSAI:  I guess greater than 3.2 but I'm a little bit confused about how we are going about this.

            DR. WEISS:  We're just answering the Agency's questions.

            DR. MACSAI:  It definitely has to be greater than 3.2.

            DR. WEISS:  Dr. Bradley.

            DR. BRADLEY:  I agree.

            DR. WEISS:  Dr. McMahon.

            DR. McMAHON:  As I.

            DR. WEISS:  Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  Yes.

            DR. WEISS:  Dr. Schein.

            DR. SCHEIN:  Yes.

            DR. WEISS:  Okay.  So you have the panel's answer on that one.  Everyone agrees.

            (b).  Maximal pupil size.  The two models of the ARTISAN are intended for patients with pupil sizes up to 5.0 mm and up to 6.0 mm.  So the question on this one is what recommendations would you -- well, can you restate the question?  What is your question?

            DR. LEPRI:  I would restate the question as does the panel recommend a maximum or minimum size pupil with respect to the available model size.

            DR. WEISS:  So the panel could also say that the nighttime pupil size should not be any larger than the optic if they wanted to say that?

            DR. LEPRI:  Yes, that's fine.

            DR. WEISS:  So the way I'm going to do this is what would your statement be as regards to pupil size?  Do you think it's relevant?  Do you think it's not relevant?  Is there a maximal pupil size that you would recommend photopic, scotopic?

            Dr. Huang.

            DR. HUANG:  I prefer your last statement using the optical size up to the size of the mesopic pupil.

            DR. WEISS:  That was my statement.  I will just let you know that is based on absolutely no evidence whatsoever but that was my statement. 

            Dr. Smith.

            DR. SMITH:  At present there's no evidence to suggest that pupil size did -- it wasn't correlated to any of the visual phenomena so I'm not basing it on any evidence but nighttime pupil size of no greater than the size of the optic.

            Dr. Van Meter.

            DR. VAN METER:  The pupil size of 5 and 6 as is written here is fine.

            DR. WEISS:  Dr. Coleman.

            DR. COLEMAN:  I agree with Dr. Van Meter.

            DR. WEISS:  Dr. Casey.

            DR. CASEY:  I agree as well.

            DR. WEISS:  So I just want to get clarification, Dr. Lepri.  The way it's presently written is the pupil size, is that mesopic should not be -- it should be 5 or less if you're using the 5 mm optic and it should be six or less if you are using the 6 mm optic?

            DR. LEPRI:  That would be correct because that would be the circumstances which we would have concern for the potential --

            DR. WEISS:  Is that how it presently reads or are we now changing things by saying that?

            DR. LEPRI:  It's not in the indication statement.

            DR. WEISS:  It's not --

            DR. LEPRI:  Those are the available models.  In light of the data that was presented with the questionnaire is with respect to development of symptoms, problems, and complaints, we wanted to know if the panel had a recommendation.

            DR. WEISS:  We are sort of getting consensus here but I do want to reiterate that we don't have a lot of data to go along with our biases.  This is how a lot of us do refractive surgery but then, again, there is the one article not showing there's any correlation so we should just be careful and put some thought into it while this recommendation is being made.  Of course, biases are a stalwart part of practicing medicine.

            Dr. Casey.

            DR. CASEY:  I agree.

            DR. WEISS:  You agree?  Dr. Mathers.

            DR. MATHERS:  Respectfully I disagree.  I don't think the data supports the restriction.

            DR. WEISS:  Okay.  So one for no restriction.

            Dr. Grimmett.

            DR. GRIMMETT:  Intuitively I believe that having the lens optic smaller than the pupil size is probably a bad idea but basing it on the data in and of itself, I didn't find evidence that was the case so I agree with Dr. Mathers.

            DR. WEISS:  Dr. Macsai.

            DR. MACSAI:  I would agree with Dr. Van Meter and I would ask that the incidences of pr-op response no and post-op response yes for glare, starburst, halos as stratified by mesopic pupil size be included.

            DR. WEISS:  Can you add that later when we get into labeling recommendations?

            DR. MACSAI:  Sure.

            DR. WEISS:  Just hold that thought.

            Dr. Bradley.

            DR. BRADLEY:  I think it's clear that theory predicts that if the pupil is larger than the optic zone, you are going to have a whole slew of optical problems.  The fact that they didn't appear in this group of patients who happen to have a pupil size larger than the optical zone seems to contradict theory so where does that leave us?  Do we go with the data or do we go with theory?  I think at this point you can't make that choice with any certainty.  Perhaps that has to be laid out to the patient.

            DR. WEISS:  So you might not put the recommendations in there but you might put in labeling that there is no information as to the impact of the optic size versus the pupil in terms of things?  Is that sort of what --

            DR. BRADLEY:  You can state the data of the study but I think it would be prudent also to mention that theory says there should have been effect.  It's a bit odd that they didn't find it.

            DR. WEISS:  So you would not put in there that it is limited in terms of the preexisting pupil size?  You're putting data in the labeling as opposed to saying this is contraindicated if you have a 9 mm pupil and using a 6 mm optic?

            DR. BRADLEY:  Correct.

            DR. WEISS:  Dr. McMahon.

            DR. McMAHON:  I feel as Dr. Bradley does.

            DR. WEISS:  Dr. Roche.

            DR. BANDEEN-ROCHE:  I defer to my vision science colleagues.  I don't feel that the data bore very strongly on the question.

            DR. WEISS:  Dr. Schein.

            DR. SCHEIN:  I can't see any advantage to using a 5 mm optic when 6 mm covers the same dioptic range.

            DR. WEISS:  If you have an 8 mm pupil is that a contraindication for getting this lens?

            DR. SCHEIN:  I have no idea.

            DR. WEISS:  I'm going to have a poll on this one, too.

            Dr. Grimmett.

            DR. GRIMMETT:  Dr. Grimmett.  I'm not exactly sure the advantage of the 5 mm but just intuitively if these are myopic lenses they would be thicker at the periphery and if you have a relatively shallow anterior chamber going a smaller diameter would keep the lens further away from the corneal endothelium so maybe the 5 mm optic is meant perhaps

-- I don't know.  Perhaps it's meant better for patients with shallower anterior chambers.c

            DR. SCHEIN:  Your logic makes sense but if you are now going to restrict it to 3.2 mm or larger, that probably doesn't exist anymore as an issue.

            DR. WEISS:  I also recall, and this is not a question I ask sponsor, that one of the lenses had double the number of lens opacities and I thought it was the smaller optic.  I don't know if anyone remembers that.

            So we're going to have a poll on this one.  For those of you who want to have something in labeling or indications that this would be indicated if you're pupil size is the same size or smaller then the optic size, that was a necessary part of this.  For those of you who would like that in labeling, can you raise your hand in the affirmative?

            So Dr. Huang, Dr. Van Meter, Dr. Coleman.  And for those of you who did not vote in the affirmative, what I would like is a straw poll of those of you who would then want something in labeling to indicate the theory versus the practice.  Namely, what Dr. Bradley was mentioning, that theoretically this should make a difference, although it wasn't shown in this study.

            Basically what I see is the majority of you would like this issue addressed in labeling rather than in indications to say that for optical reasons this might make a difference.

            DR. SCHEIN:  It may.

            DR. WEISS:  It might make a difference.

            DR. SCHEIN:  May is a very powerful word.

            DR. WEISS:  But we didn't prove it in the study so this might be something you want to think about and that would be in patient labeling as well as physician labeling.

            Dr. Macsai.

            DR. MACSAI:  Dr. Macsai.  Is this the appropriate time to talk about the glare and halos and starbursts for labeling or no?

            DR. WEISS:  Coming up soon.

            DR. MACSAI:  Okay.  I'll wait.

            DR. WEISS:  Hold that thought.  We are coming up to it soon.

            3(c).  Minimum preoperative endothelial cell density.  The outcomes of ECC change was reported in No. 1 above could be used to determine acceptable minimal endothelial cell density.  I think what we're speaking about is what was brought up by Dr. Huang and Dr. Mathers, a template for --

            Perhaps, Dr. Lepri, this might be the time to mention minimal age in association with minimal endothelial cell count with that age.  Maybe we should first talk about minimal age, get a little consensus on that, and then we can go to minimal endothelial cell count that would be associated with that age.

            Dr. Van Meter mentioned 30.  Dr. Mathers mentioned 40.  Why don't we go around.  Dr. Schein.  I know this is sort of contrary since --

            DR. SCHEIN:  We are talking about labeling.  We haven't talked about the big questions yet.

            DR. WEISS:  We're not talking about labeling.  We're just talking about indications which is a separate issue from safety.

            DR. GRIMMETT:  You can only ask the five who voted yes on that option.  The other seven don't think that's the right thing.

            DR. WEISS:  You don't feel comfortable?  If you don't have an answer, you don't have to have an answer, in other words.  If you don't have an answer to that one, that's fine.

            Dr. Bandeen-Roche, do you have an answer?  No.  Dr. McMahon, do you have an answer?

            DR. McMAHON:  Not simply but I propose a different way of looking at it if you want to get around to it.

            DR. WEISS:  Sure.  Give us your way of looking at it.

            DR. McMAHON:  Again, I'm not sure if I'm comfortable with the whole provability issue but for the sake of argument, let's say we did.  One way to address this problem is to first assign a tolerance level of the number of eyes that would based upon projected extrapolations that we currently have that would reach 1,200 cells per square millimeter.

            For example, if you assigned a value over a 30-year exposure rate of, let's say, one percent, then you can draw a table from that that is composed of age and preoperative endothelial cell count to put you within that expected tolerance rate. 

            Under that circumstance you might hedge your bet, as Dr. Mathers has been trying to get to for some time.  At least in theory.  What that would do is for potentially younger individuals, and personally if we are going to do this, I would say probably a minimum of age 30, probably in the -9s as we're talking about.  You can then actually stratify for any individual.  You actually have to take into consideration some life table analysis or there might be a difference in that for men versus women.  I think the possibility to construct that kind of table would not be all that difficult to do.

            DR. WEISS:  So we're talking about is age 30 minimum -9, minimum amount of myopia, and 1,200 cell count at your death whatever your death might be and have someone figure out that actuarial table.

            DR. McMAHON:  That would be sort of -- you could either do it that way or you could just do it assigned on a 30-year exposure rate.

            DR. WEISS:  The other variable in there is what is the percentage.  Are you using 1.8 percent per year?

            DR. McMAHON:  No, I used the one percent rate of individuals reaching 1,200.

            DR. WEISS:  What is the cell loss rate per year?

            DR. BRADLEY:  Whatever the data shows.

            DR. McMAHON:  That comes from the extrapolated information we have at the moment.  As new data appears over time, those tables could be adjusted.

            DR. WEISS:  Dr. Bradley.

            DR. BRADLEY:  The issue that we have to address if we follow Dr. McMahon's suggestion is what percentage are we willing to tolerate of these eyes reaching this critical level of 1,200 count?  Is it one percent?  Is it two percent?  Is it 5 percent?  If we can give the FDA that number, then they can come up with the -- they can delineate those eyes that can safely have the procedure and those that cannot.

            DR. WEISS:  So we're going to back up one because we are adding another part to the question.  What percentage of the -- Dr. Schein, do you have an opinion on that?  If you don't, I see Dr. Bandeen-Roche does in terms of percentage of eyes that you could see getting to the minimum endothelial cell count right before they expire.

            DR. BANDEEN-ROCHE:  Actually I just wanted to follow up not on a comment about what that number should be but just if we say FDA can calculate that number, they can also calculate how variable that projection is to within lots and lots of uncertainties about the model.  That is, of course, equally important.

            DR. WEISS:  Did you have a percentage that you might have in your mind, Dr. McMahon, as far as acceptable percentage to get to 1,200?

            DR. McMAHON:  I picked a very low number, one percent based upon the uncertainties that we're dealing with.

            DR. WEISS:  You're saying one percent of patients you would like to get to 1,200 in 30 years?

            DR. McMAHON:  Yes.

            DR. WEISS:  That's pretty stringent.

            Dr. Bradley, do you have a percentage that you would want to get there in 30 years also one percent?

            DR. BRADLEY:  I would certainly refer to my colleagues who deal with these problems on a daily basis.

            DR. WEISS:  Okay.  With that deference in mind, Dr. Macsai.  Or how would you like to handle this question?  First we're going to start with age.  As long as everyone is handling everything at once, why don't we do it all in one package.  So age, number of years, and percentage you want to get to 1,200.

            DR. MACSAI:  This is quite the conundrum because you can't randomly pick age, number of years, or the actual number.  If we're going to work backwards, we look at actuarial tables, as Dr. McMahon intimated, and we say that at 75 years the average female develops cataracts and for cataract surgery we want her to have -- I'm making it up -- 1,200 cells.

            Then we take Dr. Gray's assumed -- and you know what happens when we assume -- assume the rate of endothelial cell loss and work backwards.  From that we determine the age.  That's how you do it.  I can't give you a random age or a random number but I can tell you that I think going into cataract surgery with 1,200 cells if you assume 10 percent loss from the surgery, that brings you down to 1,080, you should be able to hang in there for a while.  But then you have to look at the fact that everyone is living longer and I think it's a complicated actuarial problem that I'm not sophisticated enough to solve.

            DR. WEISS:  Dr. Lepri, if we gave you that sort of guidance and said we want to start at what was just suggested, at the older end and work backwards to then determine the age and then determine the minimal endothelial cell count, is that something that Agency could work with?

            DR. LEPRI:  From my perspective it would be but I would certainly consult with everyone here to see if they are in agreement.

            DR. WEISS:  I see --

            DR. LEPRI:  It would make much more sense taking into effect those factors that Dr. Macsai identified which are very important.

            DR. WEISS:  I see nods in the affirmative that we could work backwards.

            Dr. Grimmett, you had a comment?

            DR. GRIMMETT:  I'm clarifying Dr. Macsai's suggestion starting backwards if we specify the target cell count at death.

            DR. MACSAI:  I don't know the information.

            DR. WEISS:  Okay.  Dr. Mathers is chomping at the bit.

            DR. MATHERS:  What we are not asking them to comment on is whether we think Dr. Gray's assessment

-- what the endothelial cell loss rate is that we should assume.  Of course, we don't really know that but we have to go with the conservative, i.e., high, loss rate because it's got to account for the relatively high percentage of outliers versus the mean. 

            I do think that Dr. Gray's assumption of a two percent loss rate, which is 38 percent will have a two percent loss rate.  That's a fairly high rate and if we just start with -- if we use that we can get some table that we can at least look at.  The whole thing depends on what you think is the loss rate, 1.8, 1.9, 2.0, 3.0.  It changes enormously.

            DR. WEISS:  What I'm wondering if you're going to start with a 75-year-old woman and an assumption of a two percent loss rate are we going to allow three people to have this phakic IOL because those are the only ones who quality after we do this calculation?  I don't know the answer to that.

            Dr. Van Meter?

            DR. VAN METER:  I think you should be extremely conservative with your loss rates because, No. 1, when some of these 40-year-olds get to be 65, they might need cataract surgery for other reasons anyway and in 30 years from now there is going to be a real shortage of donor corneas.

            DR. WEISS:  Because of LASIK you're saying?

            DR. VAN METER:  Yes.

            DR. WEISS:  Dr. McMahon.

            DR. McMAHON:  I would propose that you use not only the mean but the lower quartile of those projections as your basis.  That way you have the fastest droppers and then the average as well so you have --

            DR. VAN METER:  That would be a 2.1 or 2.2.

            DR. McMAHON:  I'm talking lower quartile of that projection.  The worse guise, all right?  So that's a harder criteria to meet than the mean is.  But if those are real is what you want to know.

            DR. WEISS:  Dr. Mathers.

            DR. MATHERS:  The two percent would not quite get there but it would be close.  I certainly think that's a reasonable way to do it, too.  That's what we're talking about and I think that's a reasonable discussion point.

            DR. WEISS:  Dr. Huang.

            DR. HUANG:  I just want to clarify that endothelial density and the age is a dependent phenomenon so when you are younger, you will have a higher endothelial density.  When you are older you have a lower endothelial density so arbitrary number doesn't really justify the safety issue.  If you were going to put a age limitation, 30 years of age or higher for this surgery, then you probably should say is 30 years or higher with endothelial density of certain amount and 40 years of age.  It's a sliding scale rather than a fixed scale.

            DR. WEISS:  I think what we're presently working on is Dr. Macsai's suggestion of looking at it from the older age and working backwards and then having the agency come up with the sliding scale perhaps on a two percent endothelial cell count than to indicate what you might need at the lower age which would not be determined at this meeting because we don't know what that sliding scale looks like yet.

            Dr. Grimmett, did you have any other comments on this point?  Are you in agreement with trying to go about things that way?

            DR. GRIMMETT:  Yes.

            DR. WEISS:  Dr. Mathers, any other comments on this point?

            DR. MATHERS:  No, I've said enough on that, I think.

            DR. WEISS:  Dr. Casey?  Dr. Coleman?  Dr. Van Meter?

            DR. VAN METER:  Fine.

            DR. WEISS:  Dr. Smith?  Dr. Huang?  So what I understand is there's consensus from the panel to defer to FDA and say we have an elderly cataract patient.  Let's work backwards, use a two percent cell loss, and then calculate. 

            How many cells, Dr. Macsai, do you want this cataract patient -- what percentage of people should have a 1,200 cell count before -- what is the Agency using for the cell count when this 75-year-old woman has cataract surgery?  What is her cell count?  What do you want it to be?  If I don't hit you to get your number when they're 30, I'm going to hit you to get their number when they're 70 or 75, whatever.

            Dr. Schein.

            DR. SCHEIN:  If you're fishing for a number, 1,600.

            DR. WEISS:  1,600.  And what percentage of people do you want to have 1,600?

            DR. SCHEIN:  Well, it gets to the endothelial loss with cataract surgery.  Mean is around 10 or 12 percent.  Mean. 

            DR. WEISS:  Okay.

            DR. SCHEIN:  I think about 20 percent --

            DR. MACSAI:  That's 2.5 percent per year.

            DR. SCHEIN:  They lose that acutely and that's the mean.  I think even if you were down to a quartile, it's much more than 10 percent.

            DR. WEISS:  You know what?  Dr. Lepri and also the Agency, do you require that level of detail from us or you do not?  Because if you do not, I don't want to go there.  If you do not, fine, we're not going there.  That's easy.

            DR. BRADLEY:  Just to make a point, although it seems imminently sensible for us to lay out the guidelines the way we have and for the FDA to do the calculations, we should be aware that we may end up approving a device for which nobody is qualified to have it.

            DR. WEISS:  I had three patients that you've gone down a couple of notches.

            Dr. Lepri, is there any other information you need for us on Question 3?  Otherwise, we'll go on to labeling recommendations.

            DR. LEPRI:  I think we go on to Question 4.

            DR. WEISS:  Okay.  So now Question 4.  Do the panel members have any additional labeling recommendations?  Dr. Macsai, now is the time.

            DR. MACSAI:  I have to wake up.  Okay.  I would want the table of pre-op response no, post-op response yes, symptoms of glare, starbursts, halos included in labeling for patients and physicians with the mesopic pupil size as the segregation tool.

            DR. WEISS:  So we are going to go around the table in terms of individual panel members and any labeling additions.  We'll start with Dr. Huang.  No?  Dr. Smith.

            DR. SMITH:  Janine Smith.  I would like the panel to think about whether they would like to include any labeling recommendations regarding the patient having failed contact lens wear, the patient not able to get full vision correction, whatever their potential vision is, because these are the high myopes that we're talking about with contact lenses so that these people would have explored every other option for vision correction before proceeding to having the surgery.

            DR. WEISS:  I think you should just list alternatives rather than forcing someone to try contact lenses.  I think the sponsor has in their handbook listed the alternatives of refractive surgery, RK.  I believe they must have listed contact lenses. 

            I don't think they listed orthokeratology but that is a much lower myopic range so it probably would be irrelevant.  I personally, and we can get everyone else's opinion, don't think you should have to force someone to try contact lenses before they have this.  Does anyone feel that you should, that one of the indications should be contact lens failure?

            Dr. Van Meter.

            DR. VAN METER:  I would just take that.  One of the things that I would suggest is since there was some difficulty in refracting the really high myopes and some of that led to lens exchanges, it might be worth trying to do a contact lens refraction on these patients diagnostically to pick the lens power.

            DR. WEISS:  Good suggestion.  That's a very good suggestion.

            Dr. Coleman.

            DR. COLEMAN:  For labeling?

            DR. WEISS:  Yeah, did you have any other labeling additions?  Dr. Smith, Dr. Van Meter, any other labeling?

            DR. VAN METER:  No, ma'am.

            DR. WEISS:  Dr. Coleman.

            DR. COLEMAN:  Yes, I do.  For the draft directions for use, page 10, they have for precautions medically uncontrollable glaucoma.  I don't think that was shown.  I would just say 8 should be glaucoma.

            In addition, for No. 7 they say secondary glaucoma and I'll just tell you what I think it should be.  It should be elevated eye pressure has been reported occasionally in patients who have received lens implants.

            DR. GRIMMETT:  What page are you on?

            DR. COLEMAN:  I'm on the labeling.

            DR. GRIMMETT:  Labeling?  Okay.  Just so I can transcribe. 

            DR. COLEMAN:  Page 10.

            DR. GRIMMETT:  Thank you.

            DR. COLEMAN:  So No. 7 is elevated IOP has been reported occasionally in patients who have received lens implants.  I have deleted "with controlled glaucoma" because these patients didn't have it.  In addition, deleted "secondary glaucoma" because that wasn't really demonstrated.  Actually, they had elevated intraocular pressure in patients who may or may not have had glaucoma because they didn't look for it so I deleted "with glaucoma" in that sentence.  Do you want me to read it again?

            DR. WEISS:  Can you write it down and then we'll give it to Dr. Grimmett so he'll have it.

            DR. COLEMAN:  The other issue is on page 11.  Do you have it right there?  They have summary of other complications and they have that there's no incidence of macular edema or pupillary block.  I disagree that there was no incidence of pupillary block because they did have a patient that they thought had presumed pupillary block and they had to redo the iridotomy so I think that should be deleted.

            In addition, they said that they had no incidence of iriditis.  I thought an inflammatory response wasn't iriditis so I thought that should be deleted because that's up there in other adverse events. 

            In addition, they said persistent raised intraocular pressure was not reported during the study and I disagree with that, too, because they had about 10 patients or approximately slightly less than one percent of subjects who needed medications for intraocular pressure control which I assume was for raised intraocular pressures.  That should also be deleted there.  It should be mentioned that about less than one percent of the patients did need medications for a long-term intraocular pressure control.

            In addition, I also would suggest that they include that the effects on patient's risk of glaucoma in the future unknown.  In addition, I think they should include the effect on the drainage angle is unknown because they didn't do gonioscopy so you really can't state what's happening with that.

            Then in terms of patient labeling, are you ready for that?

            DR. WEISS:  Just with pity to Dr. Grimmett, if you can just describe some of these things.  He's doing pretty well.

            DR. GRIMMETT:  My college note taking helps me here immensely so I did pretty well.  I got those.

            DR. COLEMAN:  Okay.  Page 12 for the patient labeling is very similar warnings which would be glaucoma instead of medically uncontrollable glaucoma.  Precautions would be elevated eye pressures have been reported occasionally in patients who receive lens implants and the intraocular pressure of patients should be monitored postoperatively.  Once again, I deleted all reference to glaucoma because they didn't really show whether or not patients had glaucoma or not.

            Then I thought in the index on page 17 they should include glaucoma and they should also include intraocular pressure or eye pressure, whichever one they used.  Thank you.

            DR. WEISS:  Thank you.

            Dr. Casey.

            DR. CASEY:  No additional recommendations.

            DR. WEISS:  Dr. Mathers.

            DR. MATHERS:  No additional recommendations.

            DR. WEISS:  I just had a couple in the patient booklet as well.  On page 8 under benefits of the ARTISAN IOL it says, "It may allow you to see clearly at far distances."  I would rather say improved distance vision but maybe that is being too picky. 

            The more important one was actually under precautions.  I thought it was interesting on page 13 the sponsor writes, "The safety and effectiveness of the ARTISAN IOL for the correction of near sightedness have not been established in patients."  Gee, that's interesting to put.  I don't think that is something we would want in there if it ends up getting FDA approved saying that the safety and efficacy has not been established.  I was surprised.  You guys should have someone reread your stuff because that's not a good one. 

            I think we should have something there and I'm sure someone else will speak to this in terms of the long-term effect on corneal function and the potential risk for corneal edema has not been determined because of the lack of long-term data and that in short-term that the endothelial cell count has decreased in the three-year period of time and we don't know what that decrease is going to be or what the curve is long-term.  Obviously to wordsmith it.  The FDA will wordsmith it a lot better than I just did.

            Dr. Grimmett.

            DR. GRIMMETT:  Nothing to add at this time.

            DR. WEISS:  Dr. Macsai.

            DR. MACSAI:  I would echo your sentiments about the corneal endothelial cell loss rate being not established as safe.  I would also not be happy if this device was marketed as that which improved contrast sensitivity and improved lines of vision one can read because I think those were the results of magnification and simply taking a spectacle lens which mine when they are dirty do decrease my contrast and eliminating the refractive index problems.  I wouldn't like that to be a took that is used to promote this device.

            DR. WEISS:  The only way I could see you address that is if you said either contact lenses or phakic intraocular lenses may improve vision over spectacles.  You could indicate that if you wanted.

            DR. MACSAI:  That would be a good way to do that.

            DR. WEISS:  I would also just add -- I assume someone else will but the same issues with lens opacities long term would go with cornea.  We don't know what it's going to be 20 years down the line for lens opacities.  Anyone can add anything else they want because 20 years down the line actually we don't know any of these things but certainly lens opacities and corneal endothelial changes are the highest concern it seems.

            Dr. Bradley.

            DR. BRADLEY:  First I would reiterate a couple of things.  I think the product should be clearly stated that when switching from spectacle correction to this IOL there will be magnification for myopic eyes.  That magnification will lead to potential improvements in visual acuity.  Make it clear why those improvements are occurring.

            Second point, and perhaps the most important one, I think both the physician labeling and, perhaps more importantly, the patient labeling should include a very clear understandable statement describing our concerns about the future risks of this product and that, in fact, the criteria for who and who might not be eligible for this procedure are based upon those concerns. 

            Somehow that should be communicated to the patient and, therefore, the risk that they -- the perceived risk that they are about to embark upon by having the procedure.  Somehow that risk needs to be communicated to them, although I agree at this point in time we are really just extrapolating to come up with this risk and the patient needs to know that, too.

            DR. WEISS:  Maybe that's the way to say it is we cannot extrapolate to what the risks will be with A, B, C, D, E.

            DR. BRADLEY:  No, I wouldn't say it that way because I think the fact is that we are suggesting that, indeed, the criteria for who and who is not eligible is based upon that extrapolation.  Therefore, we can extrapolate.  We are going to do it.  I don't think we can sort of palm it off and say who knows what's going to happen in the future. 

            Let them know that this panel and the FDA although we have uncertainties about extrapolating in the future have enough faith in the data to use those extrapolations to guide us in who and who cannot have this procedure.

            DR. WEISS:  I think that would be ultimately determined by the vote that takes place here.

            DR. BRADLEY:  Yeah, but you know what I mean.

            DR. WEISS:  Dr. McMahon.

            DR. McMAHON:  Nothing additional to add.

            DR. WEISS:  Dr. Bandeen-Roche?

            DR. BANDEEN-ROCHE:  Yes, certainly this does not condition what my vote will be but I would just second and third all the comments about very, very clear section being needed describing what are the risks that we are concerned about and that we have vast uncertainty about what the long-term outcomes will be.

            DR. WEISS:  Dr. Schein.  And I would indicate, Dr. Schein, you have the opportunity to suggest any premarket, post-market whatever studies because that has not -- there was not a question about that but this might be the time to say it if you want to.

            DR. SCHEIN:  First, I have a few labeling comments that are based on the draft that was given to me.  The first has to do with adverse event recording.  The number 662 is listed there and that excludes some of the patients that underwent the procedure in the study.  And the rates as written imply that they are based on a full cohort of 662 individuals.  In fact, they imply that it's a three-year study upon which the adverse event rates are calculated and that's not accurate.

            The term "nonadverse event" I have trouble with that in the main document but to find that in patient labeling I thought was really wrong.  I would make the same suggestion as before, that they simply list how many individuals.  Not just eyes but how many individuals require additional refractive surgical procedures, additional surgeries or procedures to address complications such as wound leak and lens repositioning, etc., again, on a per-eye and per-person basis.

            Under complications I didn't see cataract listed.  I didn't see lens opacity listed.  Perhaps I missed it but I didn't see it under that heading.  I think that is the biggest concern in my mind is lens opacities and cataract.  When endothelial cell data is presented, I again would not limit it to the means but I would indicate the proportion of losing, 10 percent or 15 or 20 percent, some reasonable thresholds at a specific time period such as two years.

            Finally, I would delete this reference to the FDA grid for secondary implants for all the reasons that we discussed before because, again, it gives the wrong impression. 

            Do you really want me to talk about post-market surveillance?

            DR. WEISS:  I guess the way you phrased that, the answer would be no.

            DR. SCHEIN:  I mean, is this the time to do that?

            DR. WEISS:  Well, actually hold on one moment.  We are going to have Dr. Van Meter and Dr. Rosenthal, I think, is going to address that.

            Dr. Van Meter.

            DR. VAN METER:  One quick question.  Did we get the risk of dislocation from trauma?

            DR. WEISS:  Actually, that's an excellent point.  We should put that in labeling.

            DR. VAN METER:  That's not on my draft and I don't know if it was --

            DR. WEISS:  I had mentioned that should be put in labeling before and I forgot about it so thank you, Woody.  There is risk of dislocation with trauma so if you are engaging in any activities, you might want to avoid them or avoid having this lens.

            Dr. Rosenthal.

            DR. ROSENTHAL:  I would like to have a sense of the panel regarding a post-market study if the device is ultimately comes to approvability regardless of what the panel votes today.

            DR. WEISS:  What we'll do is we'll finish the labeling issues and I'm going to go on to Mr. Balo and then Ms. Such.

            MR. BALO:  I never had the labeling to review so I can't make any comments but relative to premarket, post-market usually that's done when you're voting in the conditions for the device.  You would basically state if you were doing a premark or post-market study.

            DR. WEISS:  We have to decide those things now and then we'll have our vote so that's why we are going to have everyone have their say on these issues before we have a vote.

            Ms. Such.

            MS. SUCH:  I have a few issues actually.  One is in the two and a half years I've been on this committee I've not seen us approve an age bracket where it's not been in the study.  I see that in this patient brochure we're saying about 18-year-olds being approved when the youngest group that has been used in this has been 21 years of age.  That's my first comment.

            My second comment is on putting something in there as I've heard about starbursts.  I would like to see something in there about low-level lighting and activities, that that should be a precaution using about starbursts and halos.

            The last thing -- another thing is about activities.  I don't know how to put this without saying boxing but to put something in there, a precaution.  There should be some precaution put in there about participating in activities that would be somewhat more eventful for head trauma.  That could be anything from operating a jackhammer or something that would be more likely to have that type of activity.

            I don't know that would particularly do that but you are more the experts than I but something to that effect.  Football is definitely something that you would think about or some of these type of activities.  Especially when you're talking about if they were to go ahead and do it for 18-year-olds who were still playing football or doing those type of activities.

            The other is that I looked at the glossary of this and I have to say that the glossary is very, very, very short and inadequate.  Someone really needs to wordsmith this in a way that somebody could actually use the glossary.  I have to commend, though, the people that did the introduction to this patient brochure.  The beginning of this brochure was very thorough. 

            It gave a lot of information.  It gave people a good understanding of what the device was about and explains how the eye worked and it gave a very comfortable lay explanation.  Then when it went on further and it went into the precaution, who should, who shouldn't, warnings and things like that, terminology was used that quite frankly I tried out on people that work at the Lighthouse, a place for vision, and I lost over 80 to 90 percent of the people when I asked terminology. 

            I think that says a lot so you need to go through and look at things that are specifically visually connected and go through and put that in the glossary or don't bother putting a glossary in.  I really think a glossary is important that you do put in because people are going to look at that and they are just going to blank out.  They really want to know what these words mean.  I would put in the beginning of this, "See glossary for further terms."  That's all the comments I have.

            DR. WEISS:  Thank you.  One thing I just wanted to add with the labeling, we were talking about cataract and corneal decompensation.  Just to the Agency, if you could elucidate what that meant in terms of if you have a cataract your vision goes down and you may need surgery and if you have corneal decompensation, your vision may go down and it might hurt and you might need surgery so it makes it something more relevant than something that a patient couldn't identify with.

            If we have no other labeling issues, then i'm going to go to a question on --

            Yes, Dr. McMahon.

            DR. McMAHON:  We had our discussions about some of those minimum criteria.  One of the ones was a minimum age of 30 was thrown out there.  Current labeling does say 18 or 21.  The issue is do we want to address that.

            DR. WEISS:  We can address that but from what I understood, we were going to work backwards on the age starting with an elderly cataract patient with a minimum endothelial cell count of perhaps 1,600 and then seeing what the ages would be. 

            My impression is using a two percent cell loss rate and ending up with 1,600 cells we are going to be much more conservative than what has been presented to us so we are going to have a much older age.  But it's probably smart to stipulate a minimum age if my impression is incorrect. 

            Why don't we go around.  Dr. Schein, do you have a minimum age that you would suggest for this?  If you don't, you can pass.  Dr. Bandeen-Roche?

            DR. BANDEEN-ROCHE:  No.

            DR. WEISS:  Dr. McMahon.

            DR. McMAHON:  30.

            DR. WEISS:  Dr. Bradley.

            DR. BRADLEY:  No.

            DR. WEISS:  Dr. Grimmett.

            DR. GRIMMETT:  Don't know.

            DR. WEISS:  Yes, Dr. Mathers.

            DR. MATHERS:  Even those don't know.  If you have the other stipulation, you don't need the minimum age.

            DR. WEISS:  Dr. Casey.  Don't know?  Dr. Coleman.

            DR. COLEMAN:  I don't know.

            DR. WEISS:  Dr. Van Meter.

            DR. VAN METER:  I said 30 pulling it out of a hat but I would certainly defer to the table that we're talking about developing.

            DR. WEISS:  But you wouldn't feel uncomfortable going down to 18, would you?  Oh, you would?

            DR. VAN METER:  I would feel uncomfortable going down to 18.

            DR. WEISS:  Uncomfortable going down to 18.

            Dr. Smith.

            DR. SMITH:  Refer to the table.

            DR. WEISS:  Does anyone feel comfortable going down to 18?  If anyone does, can you raise your hand?  You feel comfortable going down to 18?

            DR. MATHERS:  Uncomfortable.

            DR. WEISS:  Dr. Huang.

            DR. HUANG:  I don't know.

            DR. WEISS:  I think for minimum age for Agency we don't know it but you're getting a sense of the panel it would be older than what was presented rather than younger.  Certainly it wouldn't be 18 if the youngest patient they did was 21.  At least the people who have expressed an age it has been 30 to 40, in that range, for those who expressed an age.  The majority don't have the knowledge or don't want to express an age.

            We are going to then go on to final question before a 10-minute coffee break before we have the open public hearing session, closing comments, and then the vote.

            The final question here is post-market study.  Ralph, we don't really need to talk about pre-market study because that's a separate issue.  Post-market study.  Dr. Schein, you would like a post-market.  Can you tell us about this?

            DR. SCHEIN:  I think this device satisfies the criteria that I would suggest are appropriate to request a post-market surveillance.  Some of those criteria would be that there's a relatively large population at risk for which there are alternative treatments that are already available with lower risk profiles. 

            The serious complications that we're concerned about, although relatively rare, can be very devastating.  The sample size of the premarket studies, 300 patient or 600 eyes or anything in that range, is really inadequate to get an accurate estimate of complications that may be occurring in one in 100, one in 300, one in 500, complication rates that would be very important were this applied to a large population.

            The other condition is that there's concern that the rates of complications may actually be different once the product has been approved and the population of patients is larger and the population of surgeons is larger. 

            All of those things taken together, I think, suggest that a post-market surveillance study is appropriate here.  As I said before, the purpose of this is to pick up very series events which are easy to pick up but deemed by everyone to be important such as cataract surgery, corneal transplantation surgery, need for explantation of the device, retinal detachment, perhaps one or two others that others might think about in a large population.  To define large, again, I would have to do some calculations but in the order of more than 1,000.

            DR. WEISS:  You want a post-market study going out how long?

            DR. SCHEIN:  Well, I would say two or three years.

            DR. WEISS:  So you would like five to six years data?

            DR. SCHEIN:  No.

            DR. WEISS:  An additional two to three years?

            DR. SCHEIN:  No, no.  This is not on the existing cohort.

            DR. WEISS:  A new cohort.

            DR. SCHEIN:  By definition this is a different cohort after the procedure is penetrated successfully into the market and there's a larger distribution of patients and doctors.  It has nothing to do with the existing cohort.

            DR. WEISS:  A new cohort, five to six -- how many years?

            DR. SCHEIN:  Two to three years.

            DR. WEISS:  Two to three years of a new cohort with a number of patients being determined by the Agency.

            DR. SCHEIN:  Well, we're talking about the Agency.  Based on the way to go about it is to simply look at the precision of an estimate so if you want to be able to say confidently that retinal detachment is one per 100 and that would be unacceptable, that would generate a certain sample size.  We have to go through a process to get there.  I don't want to make up a sample size sitting here.

            DR. WEISS:  Does the Agency need anymore information on that or not? 

            DR. ROSENTHAL:  I'd like a sense of the panel on the concept.

            DR. WEISS:  The concept for the panel, and please add to this, we have to suggest that we have the least burdensome for the sponsor so this is because you have continued concerns that it might be voted to be reasonably safe and efficacious but, indeed, it might not be reasonable to believe safe, so then you're doing this study.  I would assume that is the reason for this.  Why do you want the post-market?

            DR. SCHEIN:  For those five or six reasons that I listed a moment ago.  Basically I have concern about serious adverse events not being adequately addressed by the premarket study.

            DR. WEISS:  So you are concerned it may not be reasonably safe.

            DR. SCHEIN:  For example, distinctly burdensome to propose a study that went out long enough to detect long-term corneal edema rates.  I think that is infeasible and impractical.

            DR. WEISS:  Again, Dr. Rosenthal, correct me if I'm wrong.  Obviously if you had extreme concerns about safety, then you would not be voting in the affirmative for the PMA because to pull a device, while you can do it, is quite difficult.  Is that correct, Ralph?

            DR. ROSENTHAL:  No.  I mean, if a device ultimately goes on the market that is shown to be in some aspect unsafe, it can be recalled, Dr. Weiss.

            DR. WEISS:  But if you feel -- however, if you feel it's unsafe based on this data, you would not be voting in the affirmative for this PMA.

            DR. ROSENTHAL:  If you feel it's unsafe based on this data, then it does not have a reasonable assurance of safety and efficacy and you will vote not approvable but you won't need a post-market study because it didn't get approved.

            DR. WEISS:  It didn't get to market.

            DR. ROSENTHAL:  But if it ultimately -- if the company ultimately fulfills the conditions under which you have voted not approvable and then gets approvable nod, then knowing about whether the panel would think a post-market study is indicated would be very important to us.

            DR. WEISS:  Dr. Schein.

            DR. SCHEIN:  I'm not sure, Dr. Rosenthal, I understand that completely.  Were you saying that a sponsor completes a PMA and that it is then either safe or effective or not and if it is safe and effective, there's never any -- there's no calling for further data?

            DR. ROSENTHAL:  I'm not saying that at all.

            DR. SCHEIN:  I misunderstood.

            DR. ROSENTHAL:  I'm saying if there's not a reason -- if this panel does not feel there is a reasonable assurance of safety and efficacy, they will not give an approvable or approvable with conditions recommendation.  Therefore, we'll get not approvable.  With a not approvable recommendation we cannot ask the sponsor to do a post-market study --

            DR. SCHEIN:  Now I understand.

            DR. ROSENTHAL:  -- because it hasn't gotten a nod to go on the market.  If they fulfill the conditions which you feel needs to be fulfilled to show a reasonable assurance of safety and efficacy, because we have to provide that to the sponsor, if they get a not approvable recommendation, then if they ultimately fulfill those conditions, then I would like to know whether or not this panel would feel that a post-market study would be indicated.

            DR. SCHEIN:  So to comp my thoughts, whether the device is deemed approvable today or at some future date, my argument stands that I think a post-market surveillance study would be necessary.  I think a good analogy is the extended wear contact lens for which such a study was mandated for complication of ulcerative keratitis when, indeed, there was not a single case of ulcerative keratitis in the premarket study.

            DR. WEISS:  Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  Yes, I would just -- I guess I would just voice my concern that the endothelial cell count data is such that at this point I don't feel like I can certify reasonable assurance of safety.  Thus, I feel more of that data is necessary. 

            We've heard today that, you know, data that would suggest a leveling out or that would satisfy people's concerns really doesn't exist.  I think maybe a few more years of data would be helpful.  It might indicate a leveling out.  It certainly would provide more individuals for the sorts of subset analysis that would feed into a grid.

            DR. WEISS:  So two to three year post-market.

            DR. BANDEEN-ROCHE:  Or pre-market.  I'm just putting either one on the table.

            DR. WEISS:  Dr. McMahon.

            DR. McMAHON:  In the two areas in the post-market environment that I'm concerned with is the endothelial cell loss which I don't know if that's practical to track in a post-market study surveillance.  And the second is cataractogenesis which probably is.  If it can be done for endothelial cell loss, yes, if that's not unduly burdensome.

            I'll just step aside for one second and ask a question that pertains to the previous question in labeling, and that is in our discussion we talked about minimum refractive errors being changed from -5 to -9.  Did that officially get into the labeling?

            DR. WEISS:  That's an excellent point.  That's an excellent point.  Let's just quickly go around with the post-market and then let's go back to the minimal refractive error.  I thank you for bringing that to my attention.

            Dr. Bradley, premarket, post-market, nothing?

            DR. BRADLEY:  Nothing.

            DR. WEISS:  Nothing.  Dr. Macsai.

            DR. MACSAI:  My concerns have been addressed.

            DR. WEISS:  So you need neither premarket or post-market?

            DR. MACSAI:  No, by the previous comments.

            DR. WEISS:  Which one do you want?  Do you want a premarket or a post-market or you do not?

            DR. MACSAI:  You mean I have to pick?

            DR. WEISS:  Do you want either of those or you are satisfied with not needing either of those?

            DR. MACSAI:  I want either.  I want both.

            DR. WEISS:  Okay.  So you would like either a premarket or a post-market. 

            Dr. Grimmett. 

            DR. GRIMMETT:  I agree with Dr. Schein, affirmative post-market.

            DR. WEISS:  Post-market.  Dr. Mathers.

            DR. MATHERS:  Post-market.

            DR. WEISS:  Post-market.  Dr. Casey.

            DR. CASEY:  Post-market.

            DR. WEISS:  Post-market.  Dr. Coleman.

            DR. COLEMAN:  Both.

            DR. WEISS:  Dr. Van Meter.

            DR. VAN METER:  I'm not sure I understand the benefit of additional specular cell counts the way we're doing them because I think they have muddied the water and I think more data of what we've got wouldn't necessarily elucidate.  It might be helpful to see maybe one more year's data on the cohort of patients that have already had the lens to be sure that nothing changes but I don't see a need for post-market surveillance.

            DR. WEISS:  Dr. Smith.

            DR. SMITH:  Both.

            DR. WEISS:  Dr. Huang.

            DR. HUANG:  Post-market.

            DR. WEISS:  Post-market.  Just sort of for clarification, if you need further premarket data, that is, speaking that you would not be voting for approval, if you needed a post-market, that would be a potential condition that would get voted on separately from a main motion. 

            Dr. Rosenthal, correct me if I'm wrong.

            DR. ROSENTHAL:  You may vote for approval and still require additional pre-market analysis.

            DR. WEISS:  So do we need specification from those who wanted premarket as far as what they want?

            DR. ROSENTHAL:  No, I think we have a sense of what they want.

            DR. WEISS:  You have a sense of what they want.  Okay.  And would that then be listed -- that would then be listed as a condition?

            DR. ROSENTHAL:  If it was approved.

            DR. WEISS:  If it was approved.  If the main motion was approvable with conditions, that would be one of the conditions.

            DR. ROSENTHAL:  If not approvable, it would be one of the conditions that the company would have to fulfill to make it approvable.

            DR. WEISS:  Thank you for that clarification.

            Now, we are going to go with one last and I think this is the last hopefully before the coffee break, is a minimal refractive error that you would consider for implantation of this lens.

            Dr. Schein.

            DR. SCHEIN:  Nine.

            DR. WEISS:  Nine.  Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  Defer.

            DR. WEISS:  Defer.  Dr. McMahon.

            DR. McMAHON:  Nine.

            DR. WEISS:  Dr. Bradley.

            DR. BRADLEY:  I would select the mean suggestion of the panel.

            DR. WEISS:  There's one in every group.  Dr. Macsai.

            DR. MACSAI:  Nine.

            DR. WEISS:  Dr. Grimmett.

            DR. GRIMMETT:  Ditto.

            DR. WEISS:  Dr. Mathers.

            DR. MATHERS:  Nine.

            DR. WEISS:  Dr. Casey.

            DR. CASEY:  Nine.

            DR. WEISS:  Dr. Coleman.

            DR. COLEMAN:  Nine.

            DR. WEISS:  Dr. Van Meter.

            DR. VAN METER:  Eight.

            DR. WEISS:  I stand corrected.  There's two in every group.

            Dr. Smith.     

            DR. SMITH:  Nine.

            DR. WEISS:  And Dr. Huang.

            DR. HUANG:  Eight.

            DR. WEISS:  Let me just poll the panel.  Does anyone here need a coffee break for 10 minutes or not?  I don't see any affirmatives so we're forging on.  Open public hearing session.  Is there anyone who -- we have someone.  Yes, please.  If you could identify yourself.  Seeing that many of my colleagues have just abandoned the ship, why don't we take that 10-minute coffee break and we'll be back here in exactly 10 minutes to hear your comments.

            (Whereupon, at 4:36 p.m. off the record until 4:45 p.m.)

            DR. WEISS:  So if those of you who are here could take your seat we're going to be starting in just a few minutes.  If you could make your comments brief, we are going to have the open public hearing session.

            DR. JOHN:  Ready?

            DR. WEISS:  Yes.

            DR. JOHN:  Hi.  I'm Maurice John, an ophthalmologist from Louisville, Kentucky.  I started implanting these lenses in October '98 and have done over 200 of them.  I would just like to make a few disjointed points.

            First of all, there was some criticism because patients were done outside of the 20/40 range.  I would point out that those are the patients who benefit the most from this and those are the people you should be improving. 

            They are 20/50, 20/60 from myopic degeneration because there is a huge chance that they are going to have an improvement in their best correctable vision.  I have already had one patient who actually was able to get a driver's license, a 45-year-old business owner who went from 20/80 to 20/60.  This is wonderful for those patients.

            Also, the panel should be aware that right now refractive surgeons do not have many alternatives.  I'm not a big proponent of clear lensectomy for myopes and I don't believe in it but that is being done and they are giving laser procedures done both PRK or ASA type procedures and LASIK most of which are being done with a blade with variable depths.  This is a fabulous alternative compared to what is being done out there and it's going to be done if they do not have some other alternative.

            A prudent doctor, which I consider myself on most days, would certainly have your patients back every year for endothelial cell counts.  I think that is going to address some of those concerns and that should probably be in your information that the FDA has put out encouraging patients to do that.  Why wouldn't you do that?

            One of the wisest things you've done today, and you may not be aware of it, but from my clinical experience was that you suggested that the anterior chamber depth be greater than 3.2 mm.  I absolutely agree with you on that.  This lens likes a little space and I think 3.3 and greater is very reasonable and appropriate and it's going to work well.  It's going to cut down on some of these complications that you see.  I'm quite sure of that.

            As far as this lens in my six years and four months experience with it causing cataracts and retinal detachments, retinal detachments are the least of my concern for this lens that it's going to call retinal detachment.  I do not believe that for a second.  As far as cataract, that's only the least of my concerns.

            I would point out I do not consider cataract a benign complication of this lens and that's why I don't implant other lenses.  There is a reason that 60 plus percent of the free market out there outside of the United States is using this lens when they have the options of using everything else that is out there. 

            Also, I think you are making a mistake in limiting this to 9 diopters.  There are patients with incredibly thin corneas who are candidates for significant haze with a PRK procedure or cannot have a blade procedure or LASIK type procedure and this works well for them.  Just because there was a little variability in the accuracy of this I don't think is a reason to exclude that.  So my two cents worth.  Thank you very much.  Appreciate it.

            DR. WEISS:  Thank you.

            Dr. Rosenthal, do you have any comments?

            DR. ROSENTHAL:  I do not.

            DR. WEISS:  Are there any closing comments by FDA?  No?  Then we will have any sponsor closing comments if they have for five minutes.  Does the sponsor have closing comments?  I guess so.

            DR. STULTING:  Thank you, Dr. Weiss, members of the panel.  I appreciate your concerns about the safety and efficacy of the ARTISAN lens.  In fact, I had many of these same concerns before I became an investigator in the study.  Like Dr. Thompson, I was swayed by the international experience with the lens.  I consider myself an average surgeon and I'll never forget the day that Rick McCarley coached me through my first case in 1998.  With time I became comfortable with the surgical technique.  After this personal experience I'm convinced that an effective training program can be constructed so that the lens can be safely implanted by an ophthalmologist with average surgical skill. 

            I've gotten to know my patients who have ARTISAN lenses and I can tell you that these are some of the most grateful patients in my practice.  I'm here today because I truly believe this technology should be available to physicians and patients in the United States.

            As a resident I was taught that surgery was contraindicated in patients whose vision could be corrected with glasses and contact lenses.  I now understand the disability that high myopes actually have. 

            My first ARTISAN implant was in a fire fighter who could not wear glasses or contact lenses safely in his work.  Corneal surgery was contraindicated to him because of the degree of myopia and the corneal thickness.  Every time I see him he thanks me for the difference I made in his life.  This is not a new technology. 

            In fact, it is available virtually everywhere else in the world except the United States.  Furthermore, surgeons who have a choice select the ARTISAN lens for implantation over other technologies.  Dr. Budo who is with us today has freely chosen to implant the phakic lens for 18 years and the aphakic lens for 21 years.  In my mind this speaks volumes about the lens. 

            If it caused a significant number of long-term complications it would be abandoned in a free market.  If endothelial cell loss were a real problem with this lens, surely there would be at least one publication in the literature after implantation of 100,000 of these devices worldwide since 1986.

            Surely Dr. Budo would tire of seeing complications from his implants.  Indeed, this is the kind of post-market surveillance that impresses me.  No surgical procedure is 100 percent safe.  Balancing safety and efficacy I believe that this technology should be made available in this country to an appropriately selected patient population. 

            Age, endothelial cell counts, and refractive errors should be considered during the selection process.  I believe that the comments provided today by the panel can give good guidance to the FDA and the sponsor so that this can be accomplished.  I hope that the panel would choose to empower ophthalmologists in the United States to offer this surgical treatment to our patients particularly those who have no other option to correct their refractive errors.  Thank you.

            DR. WEISS:  Thank you, Dr. Stulting.

            We will now have the voting options read by Sally Thornton.

            MS. THORNTON:  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, or 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 by applicable publicly available information.  Safety is defined in the Act as reasonable assurance based on valid scientific evidence that the probable benefits to health under conditions on intended use outweigh any probable risks. 

            Effectiveness is defined as reasonable assurance that in a significant portion of the population the use of the device for its intended uses and conditions of use when labeled will provide clinically significant results.

            Your recommendation options for the vote are as follows:  Approval given if there are no conditions attached.  Approvable with conditions.  The panel may recommend that the PMA be found approvable subject to specified conditions such as patient or physician labeling, labeling changes -- I'm sorry, such as physician or patient education, labeling changes, or a further analysis of existing data.  Prior to voting all of the conditions should be discussed by the panel. 

            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 use prescribed, recommended, or suggested in the proposed labeling.

            Following the voting the chair will ask each panel member to present a brief statement outlining the reasons for their vote.  Thank you.

            DR. WEISS:  Thank you.  Do I have a motion?

            Dr. Schein.

            DR. SCHEIN:  I have a question.

            DR. WEISS:  Okay.

            DR. SCHEIN:  One of the conditions -- this description of approval with conditions that Ms. Thornton just read included approvable based on further analysis of existing data.  Is that correct?

            DR. WEISS:  Yes.

            DR. SCHEIN:  I just need some education.  Maybe others in the panel do as well.  What if one requested further data, as many of us have done today, and then reviewed the data and based on the review decide that no, it's not approvable.  In other words, you're in a situation now where you want to see more analysis of existing data but you don't know yet what it's actually going to look like.

            DR. WEISS:  Dr. Rosenthal.

            DR. SCHEIN:  I've never seen you speechless.

            DR. ROSENTHAL:  I've never had a question like that before.  We can handle analysis of existing data -- I mean, of data that is requested.  If it is contrary to the recommendation of the panel, we will not go along with the recommendation of the panel. 

            For example, I'm just picking, if you have 100 patients in a study -- 200 patients and you saw 100 and there was a complication rate of two percent and you said, "Well, that may be okay but I would like to see another 50," we saw another 50 and it was 15 percent, we wouldn't accept that as a reasonable assurance of safety and efficacy, if I make myself clear.

            DR. SCHEIN:  Thanks.

            DR. WEISS:  Are you satisfied with that answer, Dr. Schein, or satisfied as one can be right now?

            DR. SCHEIN:  Yes.

            DR. WEISS:  Fine.  Thank you.

            Do I have a motion?  Dr. Van Meter.

            DR. VAN METER:  I move that the ARTISAN lens be found approval with the conditions we have discussed which would include age, anterior chamber depth, specular cell count, and degree of myopia specifications.

            DR. WEISS:  I think what we can do as a motion is approvable with conditions and then what we will --

            DR. VAN METER:  Then come up with the conditions.

            DR. WEISS:  Dr. Van Meter has a motion for approvable with conditions.  Does anyone second that motion?  Dr. Huang seconds that motion.  Now what we will do is have someone propose each of the individual conditions.  We will then --

            MS. THORNTON:  We do not vote at this point.

            DR. WEISS:  We do each of the individual conditions, we vote on each of the individual conditions, and then we vote on the main motion, i.e., Roberts Rules of Order, in my room at the time.

            Does anyone have a condition?

            DR. VAN METER:  Can we just have Mike read them off since he's been scribing all these things?

            DR. WEISS:  Mike is getting some religion here.

            DR. VAN METER:  My conditions will be most likely what is on Dr. Grimmett's list.

            DR. WEISS:  If we could have Dr. Grimmett so kindly read each of the conditions he has scribed.  

            MS. THORNTON:  Yes, you can read the issues that you feel you want to enter as conditions and then we will vote on each condition individually.  We will group -- we can have one condition as labeling just to clarify that.  In that condition you can list the things that we talked about, or you want to talk about regarding labeling.

            DR. WEISS:  So basically if we are lucky enough that it was separated into labeling issues which should be at the end of the discussion, we can vote on those in one group.  Then the nonlabeling issues, for example, the lowest level of myopia, the fact that there might be premarket or post-market studies that were requested, those things are separate conditions.

            DR. GRIMMETT:  The notes here obviously are a tad schizophrenic here so I'll be jumping around.  The first condition, limit the anterior chamber depth to those patients greater than 3.2 mm.

            DR. WEISS:  3.2 and greater or greater than?  Greater than 3.2.  Do I have a second?  Dr. Smith seconds.  All those who agree with this, can you raise your hand?

            MS. THORNTON:  That's Dr. Huang, Dr. Smith, Dr. Van Meter, Dr. Coleman, Dr. Casey, Dr. Mathers, Dr. Grimmett, Dr. Macsai, Dr. Bradley, Dr. McMahon, Dr. Bandeen-Roche, and Schein in the affirmative.  That's unanimous.

            DR. WEISS:  So that condition passes.  Second condition.  If it's too difficult to separate out labeling versus the other things, it might just be more expedient if we are out of order to vote on the separate labeling if it's too hard.  If it's hard, we can just have you read off your list and we'll vote on each of them.

            DR. GRIMMETT:  I have to read them and see which is labeling.  A lot of the first part of the discussion we had labeling mixed in.  This one might be a tough one but it's the conditions for the -- I guess the dioptic range is probably easy so let's do that.  A condition is only approval for greater than 9 diopters of myopia.

            PARTICIPANT:  -9.0 to -20.0.

            DR. GRIMMETT:  -9.0 to -20.0, the full range.

            DR. WEISS:  Do I have a second?  Dr. Mathers seconds.  Those who would like the indications to read this is indicated for -9.0 to -20.0 diopters of myopia, can you please raise your hand in the affirmative.

            MS. THORNTON:  Dr. Huang, Smith, Van Meter, Coleman, Casey, Mathers, Macsai, McMahon, Dr. Schein.

            DR. WEISS:  Those who are against.

            MS. THORNTON:  Voting against.

            DR. WEISS:  And those who are abstaining.

            MS. THORNTON:  Dr. Bandeen-Roche, Dr. Bradley.

            DR. GRIMMETT:  Sorry.  I'm trying to figure out what the next condition is.  I'm on the affirmative on that one.

            MS. THORNTON:  Okay.  Dr. Grimmett voted affirmatively.

            DR. WEISS:  So we have two abstaining and the rest were affirmative so the motion passes.

            Dr. Van Meter.

            DR. VAN METER:  By way of sponsor's request to consider a lower age group, might we vote again on 8?  That would encompass another subset of patients.

            DR. WEISS:  Unfortunately that just passed.

            DR. VAN METER:  I think the question of yes or no on that was, you know 9, certainly --

            DR. WEISS:  You know what?  You could propose -8.0 to -9.0.  We have -9.0 to -20.0.

            DR. VAN METER:  I would like to propose -8.0 to -9.0.

            DR. WEISS:  Okay.  Do we have a second?  We have Dr. Huang seconding.  For those of you who would like to expand the indications to include patients with -8.0 to -9.0 of myopia, can you raise your hand in the affirmative?

            MS. THORNTON:  Dr. Van Meter, Dr. Huang.

            DR. WEISS:  Two affirmative.  For those who would like to vote in the negative, can you raise your hand?

            MS. THORNTON:  Dr. Smith, Coleman, Mathers, Grimmett, Macsai, McMahon, and Schein.

            DR. WEISS:  And those who would like to abstain can you raise your hand?

            MS. THORNTON:  Dr. Casey, Dr. Bradley, and Dr. Bandeen-Roche.

            DR. WEISS:  So that motion does not pass.

            Dr. Grimmett.

            DR. GRIMMETT:  Next condition had to do with Drs. Macsai and Mathers comments regarding determining or calculating backwards to determine the entry age which required specifying a target cell count at the time of death and assuming a two percent loss rate if I'm paraphrasing Dr. Mathers correctly.

            DR. MATHERS:  The two percent versus the lower quartile rate.

            DR. WEISS:  Are you including that in the motion?

            DR. GRIMMETT:  Well, they're different.  Lower quartile is different than assuming two percent.

            DR. WEISS:  So then if you can just make whatever motion that you would like to make and then we can have discussion. 

            DR. VAN METER:  Dr. Rosenthal suggested we could leave this up to the Agency to do.

            DR. WEISS:  In terms of the quartile versus two percent?  Ralph, what he just said that we can leave this up to Agency.  What do you -- how specific do you want us to be in terms of this motion?

            DR. ROSENTHAL:  I'd like you to give us any guidance you feel reasonable but I don't want you to go cell by cell by age by age.

            DR. WEISS:  So can you state it in the most nebulous form possible?  I think that's what we mean.

            DR. GRIMMETT:  I'll need some help from Dr. McMahon regarding the lower quartile recommendation to help me phrase that correctly.

            DR. McMAHON:  I think it would be easier just to use the two percent because they are not going to be very different.

            DR. GRIMMETT:  Speak into your microphone.

            DR. McMAHON:  I'm sorry.  We can use the two percent.  They are probably not going to be very different.

            DR. WEISS:  Or you could say two percent of a quartile whatever the Agency deems more appropriate in this case to keep it broad.  Why don't we say that?  Would that be acceptable, Dr. McMahon?

            DR. McMAHON:  Sure.

            DR. WEISS:  Fine.

            DR. McMAHON:  The Agency will do it anyway.

            DR. WEISS:  So, Dr. Grimmett, can you restate that?

            DR. VAN METER:  Are we working backward from an average cell count?

            DR. GRIMMETT:  I think a threshold minimum cell count.

            DR. WEISS:  Which was stipulated by Dr. Schein as being 1,600.

            DR. GRIMMETT:  And by Dr. Mathers as 1,200.

            DR. WEISS:  So Dr. Mathers is just trying to help us out by making it even more general that the Agency will determine the age as well as the minimal cell count from which they will work backward from, as well as whether it will be quartile versus two percent cell loss in order to determine the minimum cell counts at various ages.  That's the motion which Dr. Grimmett will repeat.  Can you just say that's the motion and then you won't have to repeat that?

            DR. GRIMMETT:  Yeah, that's the motion.

            DR. WEISS:  Okay.  That's the motion.  Who seconds that's the motion?

            DR. BANDEEN-ROCHE:  Is there time to ask a question?

            DR. WEISS:  Yes.  You can discuss it before we have a second.  Do you want to amend it?

            DR. BANDEEN-ROCHE:  I just want to ask a question which is if the long-term endothelial cell count data leveled out magically and became evident that maybe other patients could benefit, then what would happen?  Would supplement come to expand?

            DR. WEISS:  Ralph.

            DR. ROSENTHAL:  Exactly.  The company would submit a supplement requesting a change in the indications in labels.

            DR. WEISS:  So this is not written in stone.  We are working on the basis of the data that we have.

            DR. ROSENTHAL:  Working on the basis of the data you have.

            DR. WEISS:  Fine.  Do we have a second?

            DR. McMAHON:  Second.

            DR. WEISS:  Dr. McMahon seconds.  All of those who want to vote in the affirmative of what will be labeled as that motion you can raise your hands.

            MS. THORNTON:  Drs. Huang, Smith, Van Meter, Coleman, Casey, Mathers, Grimmett, Macsai, Bradley, McMahon, Bandeen-Roche, and Schein.  That's 12 votes.  That's unanimous.

            DR. BRADLEY:  I think as said that motion was almost unintelligible but I do believe the FDA understands.

            DR. WEISS:  That's why we have transcripts.

            DR. BRADLEY:  In the transcript it's going to be nonsense.

            DR. WEISS:  Maybe more intelligible than some of these meetings.

            Dr. Grimmett.

            DR. GRIMMETT:  It's my belief that the remainder of the comments are specific to labeling.

            DR. WEISS:  Great.

            DR. GRIMMETT:  There's one issue

            DR. BRADLEY:  The age?

            DR. GRIMMETT:  The age was going to be back-calculated.

            DR. WEISS:  Independently there was a discussion on an age cutoff.  The majority of the panel members had no opinion and there were two panel members that wanted a lower-age cutoff at 30.  I don't know if you feel this way anymore, Bill, who mentioned an age cutoff of 40. 

            You can put forward a motion for a lower-age cutoff if someone wants to regardless of what the Agency finds.  You can say, "Hey, I don't want it to be done in lower than this."  If that's the motion you want to make, then that's the motion you'll present.  That wasn't really totally determined in our discussion.

            Does anyone want to make that motion that there should be a lower-age cutoff?  Dr. Van Meter.

            DR. VAN METER:  I would move that the lower age be 30.

            DR. WEISS:  Is there anyone who seconds that motion.

            DR. McMAHON:  Second.

            DR. WEISS:  Dr. McMahon seconds.  Can we have a vote on having the lower-age cutoff being 30?  All of those who agree, can you raise your hand?

            MS. THORNTON:  In the affirmative Drs. Huang, Van Meter, Mathers, McMahon.  That's four.  Those against?

            DR. WEISS:  Those abstaining?

            MS. THORNTON:  Dr. Schein, Dr. Bandeen-Roche, Dr. Bradley, Dr. Grimmett, Dr. Casey, Dr. Coleman, and Dr. Smith.

            DR. WEISS:  That motion does not pass.  Dr. Macsai also abstained.

            MS. THORNTON:  Sorry.

            DR. WEISS:  That motion did not pass.

            Dr. Grimmett.

            DR. GRIMMETT:  Next condition, as Dr. Schein suggested, is a post-market surveillance study including the factors he listed which I believe include explantation, retinal detachment, cataract formation, etc., with a sample size calculated using proper statistical methods by the agency followed for two to three years.

            DR. WEISS:  Anyone second?  Dr. Schein seconds.  Can we have a vote?  All those in the affirmative, raise your hand.

            MS. THORNTON:  Dr. Huang, Dr. Smith, Dr. Van Meter, Dr. Coleman, Casey, Mathers, Grimmett, Macsai, McMahon, Bandeen-Roche, and Schein in the affirmative.

            DR. WEISS:  That passes.  Any negative votes?

            MS. THORNTON:  Dr. Bradley negative.

            DR. WEISS:  Any abstentions? 

            DR. GRIMMETT:  Let me do this one first.  There was a discussion regarding an issue that Dr. Casey brought up followed up by Dr. Macsai that the minority population was insufficiently studied, Dr. Macsai pointing out that there were sufficient patients with the suggestion to reanalyze the data on the existing minority patients out to some appropriate interval.  What were you looking for, Dr. Macsai?  To find what type of analysis?

            DR. MACSAI:  I was curious about the intraocular pressure and gonioscopic evaluation.

            DR. GRIMMETT:  Pigment dispersion?

            DR. MACSAI:  And pigment dispersion in those populations including actually those with brown irides.

            DR. GRIMMETT:  So the motion is -- the stated motion is -- they don't have gonioscopy.

            DR. COLEMAN:  Could we make it more general maybe to make it for premarket studies?  For premarket studies including further evaluation of subjects that are minority and have darker irides for gonioscopy and endothelial cell count follow-ups and intraocular pressure?

            DR. WEISS:  That could be the motion if you would like.

            DR. COLEMAN:  That would make it a bit more general.  And also stratification of the data as elucidated by Dr. Roche and Schein.  You wanted the data presented differently for premarket studies.

            DR. WEISS:  I think we're having -- what is being suggested right now by Dr. Coleman is an inclusive motion to include all the data that you would like through a premarket study.  She's trying to be inclusive.  That could be added.  You can add to that right now while she does the motion.

            DR. ROSENTHAL:  Excuse me, Madam Chairman.

            DR. WEISS:  Dr. Rosenthal.

            DR. ROSENTHAL:  If you listen to Ms. Thornton's reading, it says that it's a reanalysis of the existing data.  If you want additional patient data included in the analysis, then it can't be a condition of approval because the approval is based on the existing data but a reanalysis of the data is acceptable. 

            If you said you want a company to provide us with information on the rate of pigmentary dispersion, rate of cataract formation, rate of chronic iritis and secondary glaucoma in the patients who have already been studied, that would be a condition of approval.  If you said we want an additional 250 patients to come to three years, that cannot be a condition of approval.  That is new data.  I have the boss here, Nancy Pluhowski, who makes it absolutely clear that that's the way we have to go.

            DR. WEISS:  Dr. Schein.

            DR. SCHEIN:  Dr. Rosenthal, I think that actually clarifies my question that stumped us 15 minutes ago.

            DR. ROSENTHAL:  That I didn't clarify before.

            DR. SCHEIN:  So that if there is a desire to have two year data on a greater proportion than the current portion which we have today, you cannot approve based on that.  You have to not approve and then come back another day.

            DR. ROSENTHAL:  That is correct.

            DR. WEISS:  So can we have a motion that would make sense as far as a condition which is --

            DR. GRIMMETT:  Reanalyze existing data for minority subset to include those patients with brown irides but that's the motion.

            DR. WEISS:  That's the motion.  Do we have a second of that motion?  Dr. Casey seconds that motion.  Do we have discussion on that motion? 

            DR. GRIMMETT:  Well, the discussion would be the things that were mentioned they are looking for don't exist.  There are no gonioscopy and no one looked for pigment dispersion in the angle and those data don't exist.

            DR. WEISS:  Can we have a vote?  All those in the affirmative raise your hand.

            MS. THORNTON:  The affirmative is Dr. Smith, Van Meter, Coleman, Casey, Mathers, Grimmett, Macsai, Bradley, McMahon, Bandeen-Roche, and Schein.  That's 11.  In the negative?

            DR. WEISS:  Abstentions?  One abstention.

            MS. THORNTON:  Dr. Huang.

            DR. WEISS:  The motion passes.  To make things easier perhaps, what we can have you do is just read the rest of the things you have written.

            DR. GRIMMETT:  I think they're all labeling.

            DR. WEISS:  Even if they are labeling.

            DR. GRIMMETT:  I think they're all labeling.

            DR. WEISS:  So if you could just read them out, call them labeling and if something is not, you can circle it and we'll go back to it.  Right now we are going to be reading all the labeling conditions and we will vote on them in one group.  Labeling items.  Excuse me.  The condition which is going to be labeling items.

            DR. GRIMMETT:  All right.  There's a condition for the following labeling conditions -- items.  Wrong word.  Pardon me.  Labeling items mentioned in the labeling is that trauma is a risk factor for intraocular lens dislocation.  Example, boxing. 

            Dr. Macsai requested a report, or at least a more comprehensive report on the safety data for Group E including those patients with custom IOLs, etc.

            Perhaps through Dr. Schein there was a mention to more accurately report to the consumer the percentage and definition of the term adverse event.

            DR. MACSAI:  Can I make a motion?

            DR. WEISS:  Yes.

            DR. MACSAI:  I move that the data be basically reanalyzed to determine what the actual adverse event rate is.

            DR. WEISS:  It won't be a separate motion but what Dr. Grimmett can do is include that in his motion of labeling because we have a motion on the table now that he's reading.

            DR. MACSAI:  No, that's not a labeling issue.  It's a condition.

            DR. WEISS:  Then don't do it now.  Then hold it.

            DR. GRIMMETT:  In order to accurately report to the consumer the percentage implicit in that is to calculate it properly but we can hold that.

            DR. WEISS:  Keep on going.

            DR. GRIMMETT:  Dr. Macsai suggested properly or more completely stratifying the data by lens power for the whole group.  That is the predictability plus or minus a half or plus or minus 1. 

            Dr. Mathers suggested that in the section that the FDA is going to calculate regarding the age and endothelial cutoffs that Dr. Gray's comment that the data suggest that 38 percent of subjects have a 50 percent reduction in 20 years.  Was it 25 years?  I thought it was 20.  Okay.  38 percent of subjects have a 50 percent reduction in 25 years. 

            Dr. Bradley suggested that in the labeling include mention of the theory that when pupil size is greater than optic size there should be a problem with visual aberrations in spite of the fact that the study did not find that.

            Dr. Macsai wanted in the labeling that the glare, starburst, and halo table, those patients that said preoperatively no and they converted to postoperatively yes be included in the labeling. 

            Anne Coleman had a long list of suggestions that she has accurately transcribed onto the labeling sheets themselves that I will just include as the Coleman suggestions because it's too long.  I'm not sure I accurately transcribed it so if that is okay with everyone, I will include Dr. Coleman's glaucoma suggestions.

            DR. WEISS:  That's fine.  In the patient information booklet on page 8 Dr. Grimmett has a written comment about indicating that the patient's visual acuity at distance will be improved as opposed to using the words that the visual acuity will be clear.

            DR. GRIMMETT:  On page 13 delete the statement that the safety and efficacy has not been established if, indeed, it's approved.  The other comment is that in the labeling mentioned that the long-term risks to the endothelium has not been established.  Also comment that the short-term cell count is decreasing.

            DR. BRADLEY:  Mike, I think I made that suggestion.  I think the important thing is that the patient understand the concern that we have about those reduced cell counts.  That needs to be in the labeling.

            DR. GRIMMETT:  I have that a little bit lower.  Dr. Bradley wanted in the labelling concerns about future risks and extrapolations and the vast uncertainty about the future and health of the endothelium and what that means both to the physician and patient.  Additional labeling concern regarding future risk for retinal detachment, cataract formation. 

            Dr. Bradley added that there is a statement regarding magnification of facts when moving a myopic correction from the spectacle plane to the iris plane.  Dr. Weiss wanted in the labeling to describe in the patient labeling what it means to the patient to have corneal edema and cataract surgery if that does develop.  I may have stated this.  Dr. Weiss wanted information regarding the occurrence of lens opacities in the future is unknown.

            Dr. Macsai wanted the contrast sensitivity information clarified with a comment that the spectacle use in the pre-op testing versus iris plane IOL testing does not indicate improved contrast sensitivity following the procedure.

            Dr. Schein had some labeling recommendations.  Please correct me if I don't accurately transmit them.  There was an inference you were commenting about the total number of eyes in the study wasn't clear throughout the document that you wanted fixed in the labeling.  Also I believe there was an inference that it was a three-year study that you believe wasn't accurate in the labeling.  You want that better clarified.

            DR. SCHEIN:  You might just summarize it as improvement in clarification of study size, duration, and complication rates.

            DR. GRIMMETT:  Okay.  Good.  So stated.  Thank you.

            Dr. Schein suggested in the labeling to list the number of surgeries on a per-eye and per-person basis.  Dr. Schein --

            DR. SCHEIN:  Adverse events.

            DR. GRIMMETT:  You want adverse event reporting more complete in the labeling?

            DR. SCHEIN:  On a per-eye and per-patient basis.

            DR. GRIMMETT:  Okay.  You want adverse event reporting on a per-eye and per-person basis.  I think you stated that in the complication section you didn't see lens opacity listed?  I think there was some clarification needed regarding the term complication and adverse events.

            DR. SCHEIN:  Correct.

            DR. GRIMMETT:  Okay.  Dr. Schein suggested in the labeling regarding the cell loss data that there is a listing not just of the mean cell loss rate but the percentage of patients losing certain increments such as 10 percent of cells, 20 percent of cells at various time intervals.

            Dr. Schein suggested the deletion of the reference to the FDA grid regarding anterior chamber IOLs, that is.

            Dr. Such had four comments regarding the labeling.  She pointed out an inconsistency that the lower age range in the study was 21 years old and not 18 as was suggested in the current labeling.  She wanted a precaution regarding low-level lighting and activities.  She wanted a rework of the glossary as the terms were inaccurate and not comprehensible to the lay person.  That concludes the labeling comments that I have.

            DR. WEISS:  Thank you so much for that exhaustive list and for scribing throughout this.  Do we have a second to that motion?  Dr. Schein has seconded.  I would like to have a vote on the motion of all the labeling conditions that have just been read.  Those who would like to vote in the affirmative, can you raise your hand.

            MS. THORNTON:  Dr. Huang, Smith, Van Meter, Coleman, Casey, Mathers, Grimmett, Macsai, Bradley, McMahon, Bandeen-Roche, Schein.  Unanimous vote of 12.

            DR. WEISS:  Are there any other motions -- any other conditions that anyone would like to raise?  Dr. Schein.

            DR. SCHEIN:  I would like to raise the same issue as relevant to the labeling.  That is, we have a per-person clinically significant complication rate estimate for this procedure.  If I went back having spent umpteen hours on this, I could not tell another doctor or patient what I actually thought the cumulative complication rate was based on existing data.

            DR. WEISS:  Do I have a second?

            DR. BANDEEN-ROCHE:  Second.

            DR. WEISS:  Dr. Bandeen-Roche.  Do we have a vote?  Any discussion on this?  There is no discussion.  Can we have a vote?  Those in -- Dr. Macsai.

            DR. MACSAI:  I would like to make it clear that these are adverse events and adverse reactions because they are different things and we can't have all these definitions that are different all the time.  I had the same problem as Dr. Schein.  It was not discernible to me from the data the way it was presented to determine what is the risk to the individual of any of those.

            DR. SCHEIN:  I purposely used the word clinically significant event.  It has to be recalculated based on a reasonable consensus of which one of those things we consider clinically significant and which you would not.

            DR. WEISS:  I think the Agency probably has a sense of what you're looking for.  With that, can we have a vote?  The Agency does have a sense.  Correct?

            DR. ROSENTHAL:  Yes.

            DR. WEISS:  Okay.  Can we have a vote?  All those in the affirmative, please raise your hand.

            MS. THORNTON:  Dr. Huang, Smith, Van Meter, Coleman, Casey, Mathers, Grimmett, Macsai, Bradley, McMahon, Bandeen-Roche, Schein.  Unanimous, 12.

            DR. WEISS:  Any other conditions?  Dr. Macsai.

            DR. MACSAI:  I would like the results of both safety and efficacy of Group E to be made available to the Agency for evaluation.  It was not in the volumes I was given.  Maybe it was in the Agency's but not in what I reviewed.

            DR. WEISS:  I thought Dr. Grimmett mentioned that.

            DR. MACSAI:  As a labeling issue.

            DR. WEISS:  I thought he mentioned it as a labeling.  Does anyone else have the same recollection?

            DR. MACSAI:  I mean as a condition of approval.  I'm asking this as condition of approval.  That's different.

            DR. WEISS:  So as a condition of approval you want -- so this is basically sort of going with Dr. Coleman's motion of preexisting data that has not been analyzed.

            DR. MACSAI:  Yes.

            DR. WEISS:  So this is similar question, same data but here is another thing that you want to be looked at.  Can you just restate that motion and we'll just then have someone second it if they will and then we'll have a vote.

            DR. MACSAI:  Data on safety and efficacy for Group E should be analyzed and reviewed by the Agency.

            DR. WEISS:  Do I have a second?

            DR. McMAHON:  Second.

            DR. WEISS:  Dr. McMahon seconds.  Do we have a vote?  Can we have all those who agree raise your hand in the affirmative.

            MS. THORNTON:  Drs. Huang, Smith, Van Meter, Coleman, Casey, Mathers, Grimmett, Macsai, Bradley, McMahon, Bandeen-Roche, Schein.  Unanimous for, 12.

            DR. WEISS:  Does anyone have any other conditions?  If not, then --

            DR. VAN METER:  Ms. Chairman, we at one time discussed -- we discussed contact lens refraction for the high myope group.  This need not be a requirement but I would like for it to be a suggestion in the physician pamphlet suggesting that a contact lens refraction be used to determine -- suggested but not requiring that the contact lens refraction be used to determine the power in the high myope say over 12.

            DR. WEISS:  Do I have a second?  Dr. Huang.  Any discussion?  Dr. McMahon.

            DR. McMAHON:  Are their nomograms going to be modified from that since we're dealing with a different refractive swing?  I understand your point.  The issue is is that a burdensome thing that is unreasonable?

            DR. WEISS:  Well, it's burdensome only if you have a requirement of the company to give you more data.  This is more of a recommendation in labeling.  Since there is no data on this, you can say it's possible that it will improve your accuracy but we have no data whether it will or not so you can't put that in there.  It's possible it will improve your accuracy and it's not putting any burden on the company.

            DR. BANDEEN-ROCHE:  Could you please restate the motion?

            DR. VAN METER:  I would like to suggest that a contact lens refraction could be used to improve the accuracy of the IOL power prediction in higher myopes.  I'm thinking 12 or 14 as a number beyond which it might be helpful.

            DR. WEISS:  And that is a labeling issue that was not mentioned and that would just be put in the physician's handbook that it might be helpful.  Anyone have a second?  Dr. Huang.  Can I have a vote?  All of those who would like that to be put in the physician's handbook can you raise your hand?

            MS. THORNTON:  Voting for, Dr. Huang, Smith, Van Meter, Coleman, Casey, Grimmett, Macsai.  That's it.

            DR. WEISS:  All those who would like to vote against?

            MS. THORNTON:  Dr. Schein is voting against and Dr. Mathers.

            DR. WEISS:  Any abstentions?  That passes.  Any other motions?  Not motions, excuse me.  Any other conditions?  If there are no other conditions, then we will have a vote on the main motion.  We have already voted on each of the conditions.  I will remind you the main motion is a vote for approvable with conditions so that is what we will be voting on now.  For those who would like to vote in the affirmative that PMA P030028 should be approved with conditions, can you please raise your hand?

            MS. THORNTON:  Voting for Drs. Huang, Van Meter, Casey, Mathers, Bradley, McMahon.  One, two, three, four, five, six.

            DR. WEISS:  Those who would like to vote against, can you raise your hand?

            MS. THORNTON:  Voting against, Drs. Smith, Coleman, Grimmett, Macsai, Bandeen-Roche, and Schein.  That's six against.  This is your day, Dr. Weiss.

            DR. WEISS:  I would say might think this is the privilege of the chair.  In this position I would say it's the burden of the chair but I will cast my vote in the affirmative for approvable with conditions.  So the PMA as P030028 has passed with approvable with conditions.  I will have a polling of the panel votes.

            Dr. Huang, if you could just give us the reason why you voted the way you did.

            DR. HUANG:  I feel this device offers a reasonable alternative for the high myope patient and has adequate safety and efficacy.

            DR. WEISS:  Dr. Smith.

            DR. SMITH:  I feel that based on the information available to me today and the data available, I was unable to estimate overall risk of clinically significant complications on a per-person basis and had existing concerns about extended endothelial cell loss.

            DR. WEISS:  Dr. Van Meter.

            DR. VAN METER:  I voted approvable with conditions and actually made the motion.  My thinking is that it is definitely effective.  It is safe within a subset of populations who have no other alternatives and for whom the benefits outweigh the risks with appropriate labeling.

            DR. WEISS:  Dr. Casey.  Dr. Coleman.  Excuse me.

            DR. COLEMAN:  I voted against approvable with conditions because although I felt the device is effective, I did not have reasonable assurance that it was safe because I need additional data to be collected.

            DR. WEISS:  Dr. Casey.

            DR. CASEY:  There is no doubt that there's a need for this device.  Myopes of -9 and above within corneas are not candidates for LASIK.  Contact lens intolerance that I've seen in these patients.  People who develop ulcers need another option. 

            While the data may not have been conclusive, I think certainly the trend was that it probably is efficacious and probably is safe.  I think that when you take all that into consideration with the world experience and the conditions that we made today, I gave my vote in favor with conditions.

            DR. WEISS:  Dr. Mathers.

            DR. MATHERS:  I voted for approval with conditions knowing that there are risks associated with endothelial cell loss and other problems associated with its use.  But I think that it can be used wisely and reasonably safely within a confined population that have no other good alternatives and clinicians should have this product available to them which is available all over the world otherwise.  We can do so safely and wisely if we guide them appropriately.

            DR. WEISS:  I voted for approval with conditions because it was obvious from the panel discussion that the data that we needed to determine things definitively would not be available and by appropriate restrictions and cautions through monitoring a minimal endothelial cell count and corresponding with the patient's age I hope that we can protect the patient population from endothelial decompensation while giving them the benefit of this exciting technology.

            Dr. Grimmett.

            DR. GRIMMETT:  I voted against the motion because I was unconvinced of a reasonable assurance of safety based solely upon the data presented in the FDA study.  Dr. Gray mentioned that based upon the current endothelial cell data, 38 percent of patients have 50 percent reduction over a 20 to 25-year period, an inference that is worrisome and does not convince me that this procedure is safe.  Given my opinion that the endothelial data does not provide a reasonable level of safety, I cannot allow a subset of patients no matter how stringent the entry criteria to undergo that risk for a cosmetic elective refractive surgical procedure.

            DR. WEISS:  Dr. Macsai.

            DR. MACSAI:  I voted no.  After analysis of the data presented by the sponsor, there remain real questions about the endothelial cell loss rate in patients that have the ARTISAN phakic IOL implanted.  As a result, I feel the sponsors have not established a reasonable assurance of safety of this device.

            DR. WEISS:  Dr. Bradley.

            DR. BRADLEY:  I voted approvable with conditions.  The device is clearly highly effective.  It also clearly comes with some risks.  The risk is small and as long as we can preselect or eliminate potential patients who have the higher risk and communicate to those who are going to have the procedure what risks they are taking, it seems approvable.

            DR. WEISS:  Dr. McMahon.

            DR. McMAHON:  I voted approvable with conditions on the basis that it is safe on the short-term basis and efficacious.  There are significant concerns with regard to long-term safety but, however, the actions of the panel in terms of the conditions, I think, are sufficient to safeguard long-term problems if they develop.

            DR. WEISS:  Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  I voted against approval because to vote for approval would have required me to certify that I found the data certified a reasonable assurance of safety.  Key aspects were sufficiently uncertain that I could not do this to within a reasonable assurance.  In combination with the concerns of my clinical colleagues, neither could I find for above a threshold of risk benefit.

            DR. WEISS:  Dr. Schein.

            DR. SCHEIN:  I voted not to approve based on my analysis of the data that was currently available today which I thought a follow-up of just over 50 percent of the cohort of two years was not enough to make the determinations that we require.

            In general, I believe in not having a patronizing approach in the sense that we dictate our own personal levels of safety on the public.  On the other hand, that demands that we are able to tell the public very accurately what the risks are and then let them determine whether that risk is adequate.  I didn't feel that we were there based on what I had seen so far.

            DR. WEISS:  We are going to have comments from the industry rep. as well as the consumer rep.

            MR. BALO:  This was very interesting for me and very overwhelming because I usually don't know much about ophthalmology but I sure learned a hell of a lot today.  That's for sure. 

            I really would like to say that the sponsor and the FDA really have worked well together over many, many years to put this device on the marketplace.  I sort of agree with the comments that were made by Dr. McMahon and Dr. Mathers.  I do think there is a place for this device. 

            I think consumers should have other choices besides the choices they have today.  I think it's good that we can have open debate, that industry can present their data, and that we can come to a reasonable conclusion that provides another alternative therapy for our patients.

            DR. WEISS:  Ms. Such.

            MS. SUCH:  On behalf of the consumers I want to thank the panel for taking into consideration all the different patient concerns in the labeling that you have all expressed all day long.  Also thanks for the piece that I had put in on behalf of the consumers that you actually accepted it into the labeling as you always do.  Thank you very much.

            DR. WEISS:  You're welcome.

            Dr. Rosenthal.

            DR. ROSENTHAL:  I just want to echo Ms. Such's thank you.  I thought this was a very thoughtfully discussed.  You made your decisions based on intelligent underpinning of a thoughtful process of what the Agency is meant to do.  I am particularly thankful to those of you who called attention to protocol issues and hope that we will be able to address them in the future submissions.  Thank you very much.

            DR. WEISS:  Thank you, Dr. Rosenthal.

            Are there any other comments by members of the panel?  If not, we will have comments by Sally Thornton.

            MS. THORNTON:  I have a couple things I just wanted to go over.  These are sort of housekeeping things.  Members of the panel got these forms at their place.  Would you please fill those out and give them to AnnMarie Williams.  She is over there by the door.  She needs to get those back before you leave today.

            Also, would you please be careful.  Leave on the table only the things that you do not want for tomorrow.  Please take with you anything that you will need for tomorrow's review, discussion, any notes you've made for tomorrow's issues because overnight all of this on the table will disappear.  Please just don't make that mistake.

            I thank you very much for your attention and your time today.  It's been long.  It seems like endothelial cell data always ends at 6:00.

            DR. WEISS:  I want to thank members of the panel, the FDA, and the sponsor and this meeting is adjourned.

            (Whereupon, at 5:46 p.m. the meeting was adjourned.)