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U.S. Department of Health and Human Services

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Ophthalmic Devices Panel – May 11-12, 2000

DIVISION UPDATES
A. Ralph Rosenthal, M.D. – Director

Dr. Rosenthal announced that effective May 15, 2000 he is to be on a temporary reassignment to the Office of the Center Director . He will be absent from the Division for approximately 4-6 months during which time, Ms. Nancy C. Brogdon, currently the Deputy Director of the Division, will be the Acting Division Director.

BRANCH UPDATES

VITREORETINAL AND EXTRAOCULAR DEVICES BRANCH
James F. Saviola, O.D. – Chief

Contact Lens Clearance K000224

The Paragon HDS-OK and Fluoroperm 60-OK (paflufocon B) Rigid Gas Permeable Daily Wear Contact Lens for Orthokeratology was cleared under 510k on April 17, 2000.

The lenses are indicated for use in the reduction of myopic refractive error in non-diseased eyes. The lenses are indicated for daily wear in an orthokeratology fitting program for the temporary reduction of up to 3.00 diopters of myopia in eyes with astigmatism up to 1.50 diopters.

There is also a Note in the indications:

To maintain the orthokeratology effect of myopia reduction lens wear must be continued on a prescribed wearing schedule.

The only other orthokeratology lens that has been cleared for marketing besides this Paragon lens is the Contex lens. It is remarkable to look at the similarities in the outcome data for the two lenses:

Paragon

  • 184 (92 patients) eyes enrolled in the clinical study with 114 eyes (57 patients) completing a minimum of 3 months of contact lens wear.
  • A total of 113 eyes showed some reduction in myopic refractive error during the 3-month time period
  • The average reduction was 1.70 diopters with a range from 0.125 to 4.50 diopters.

Contex

  • 138 (69 patients) eyes enrolled in the clinical study with 110 eyes (55 patients) completing a minimum of 3 months of contact lens wear.
  • A total of 106 eyes showed some reduction in myopic refractive error during the 3-month time period.
  • The average reduction was 1.69 diopters with a range from 0.25 to 4.25 diopters.

The Paragon labeling information describes the effectiveness limitations for the lens.

  • The average wearing time required for patients was consistently about 9 hours during the entire three month study.
  • There was variability in wearing time. At the end of the study, 35% of the subjects wore the lens 8 to 12 hours while 26% wore the lens from 12 to 16 hours. Only 5% of the subjects wore their lenses from 0 to 4 hours.

When the population of subjects that had the potential to achieve 20/20 uncorrected acuity is considered – that is the eyes targeted for emmetropia, 45% achieved 20/20 at 3 months. When all eyes regardless of pre-treatment BSCVA are considered, 80% were able to see 20/40 at 3 months.

Once again, this marketing clearance does NOT mean that FDA has approved the procedure of orthokeratology. It does mean that the Paragon ortho-k lens designs may be legally marketed for the intended use described in the product labeling. It is my understanding that Paragon intends to allow qualified finishing labs to market this reverse geometry design.

Guidance Released

The Guidance for Industry, Guidance for Premarket Submission of Orthokeratology Rigid Gas Permeable Contact lenses was issued by the Office of Device Evaluation on April 10, 2000. The Office released this as a Level 2 guidance document since it contains the same information that the Division has provided interested manufacturers going back to the Contex clearance in 1998.

The shelf number for the document is 1134. It is available from the CDRH Facts on Demand or the CDRH website.

The document is intended to provide guidance for rigid gas permeable (RGP) contact lens manufacturers that submit marketing applications for contact lenses intended for use as orthokeratology devices

A discussion of the clinical testing issues for orthokeratology lenses was held at the February 12, 1998 meeting of the Ophthalmic Devices Advisory panel.

  • This guidance document identifies specific clinical protocol recommendations and data analysis tables to develop and evaluate the safety and efficacy data of these devices.
  • A large segment of the guidance document is devoted to a labeling template that includes the primary package, a package insert, a practitioner fitting guide and a two part patient booklet.
  • Detailed examples of specific labeling components required by regulation are provided.
  • A primary goal of the labeling is to communicate reasonable expectations of success to the user.
  • The guidance for preclinical manufacturing, chemistry, toxicology, and microbiology information that should be addressed in an application is incorporated by reference to the Premarket Notification (510(k)) Guidance Document for Daily Wear Contact Lenses dated May 12, 1994, or the most current version.

Copies have been sent to current Panel members, those in attendance at the February 1998 meeting, and a few of the consultant with a special interest in this area.

Since this is a Level 2 guidance, comments may be submitted at any time, but we are especially interested in receiving comments during the first 60 days that it is posted. The guidance will be revised based on review of substantive comments

INTRAOCULAR AND CORNEAL IMPLANTS BRANCH
Jan C. Callaway – Acting Chief

On March 31, 2000, the reclassification notice for aqueous shunts and keratoprostheses was published in the Federal Register. These devices were reclassified as Class II devices. The reclassification becomes effective on May 1, 2000.

Mr. Don Calogero and Ms. Ashley Boulware, branch biomedical engineers, participated in the American National Standards Institute (ANSI) and International Standards Organization (ISO) meetings in Shanghai, China. The meetings were held to discuss new standards for Refractive Implants and Multifocal Intraocular Lenses. ANSI has begun work on these standards. ISO committee members are currently voting on establishing these draft standards as New Work Items. The ISO committee membership seemed receptive to using the ANSI draft standards as starting points for the ISO standards. Draft Standards for Ophthalmic Irrigating Solutions and Endotamponades were also discussed during the ISO meeting.

DIAGNOSTIC AND SURGICAL DEVICES BRANCH
Morris Waxler, Ph.D. – Chief

On May 9, 2000, the Autonomous Technologies premarket approval application (PMA) P970034/S005, for an excimer laser for myopia < -9.00 D sphere with or without cylinder ≥ -0.5 D and < -3.00 D using laser in-situ keratomileusis (LASIK) was approved. The application was reviewed by the panel at the March 17, 2000 panel meeting.

The Sunrise Technologies premarket approval application (PMA) P990078 for the Hyperion™ Holmium Laser, which was reviewed at the January 13, 2000 panel meeting, remains under review by the Agency.

PMA PRESENTATION

PMA P930016/010 – VISX, INC.

VISX STAR S2 Excimer Laser for naturally occurring hyperopia from +0.5 to +5.0 diopters (D) of sphere with +0.50 to +4.00 D of cylinder.

Panel Recommendation by vote: Approvable with conditions: 8-0, unanimous

The conditions of approval:

  1. The laser should be indicated for a range of +5.00 diopters (D) of sphere, +4.00 D of cylinder with a maximum Mean Refractive Spherical Equivalent (MRSE) of +6.00 D.
  2. Update tables with Complete Cohort Information after a complete analysis of 12 months data. The labeling language should be formulated pending FDA analysis of all outcomes.
  3. The sponsor needs to submit an analysis of outliers to be reviewed by FDA.
  4. Labeling Conditions:
  • The sponsor should stratify effectiveness data (predictability,stability) by attempted correction and present all statistically significant findings, e.g. contact lens use, race, and gender.
  • Stability data should be included and the labeling should state that complete stability has not been obtained within the 12 month period. Long term hyperopic changes up to 0.5 D per year may be anticipated. There is a greater shift toward hyperopia with increased attempted correction (with data presented and stratified).
  • The physician and patient labeling should state the potential for instability and define and describe the outlier group.
  • The physician and patient labeling should clearly describe:
  • Retreatment – State that there is no data available
  • Pupil diameter – State that there is no data available
  • Monovision – State that there is no data available
  • Epithelial healing
  • Pain
  • Photophobia
  • Visual Acuity Recovery
  • Spectacle wear (for near and distance vision)
  • Visual function under dim illumination
  • Presbyopia
  • There should be a separate labeling booklet for hyperopia with and without astigmatism.

POSTERIOR CAPSULE OPACIFICATION (PCO) DISCUSSION

The committee was asked to discuss issues related to the design and development of clinical protocols for studies to support claims of reduced posterior opacification. The topics were as follows:

Clinical Endpoints

  • Visual function
  • Visual acuity with a loss of 2 or more lines to be considered significant
  • Claim of delay in onset is not clinically relevant
  • Quality of life questionnaire should be included

Study Controls

  • Study should control for the variables, e.g. lens design/lens material
  • No agreement on a lens to use for comparison as a control or "gold standard"
  • No historical rate exists for reference
  • Consideration of the variability in surgical technique impacting the PCO rate

Methodology

  • Evaluation of the central 3-4 mm of the capsule is important, peripheral evaluation should also be noted.
  • Sheimpflug method of measurement not as good as a retroillumination based method because of limited area that can be measured
  • Objective methods should be used for evaluation where repeatability and accountability can be measured.
  • Visual measures should include visual acuity and contrast sensitivity
  • Reasons for doing a Nd:YAG capsulotomy need to be clearly stated in the clinical report
  • Grading schemes should be standardized with consideration given to the possibility of a central reading center for results.

Clinical Protocol

  • Patients with retinitis pigmentosa, wet AMD or high risk dry AMD, or diabetic retinopathy should be excluded.
  • Diabetes and glaucoma may be excluded, but should leave it up to the company as they may want to identify a high risk subgroup in the study.
  • Conditions such as capsulorhexis tear, zonular dehiscence, posterior capsule rupture, vitreous loss, should be assessed as they could heavily affect the outcome.
  • Patients with high myopia may be problematic
  • Measurements at 1 month, 4-6 months, 1 year and 2 year at least would be appropriate.
  • The study should be randomized, internally controlled, and masked appropriately.
  • Surgical technique should be standardized
  • If PCO studies are to evaluate both the YAG capsulotomy rate and PCO incidence, then there should be should be a defined evaluation of the PCO and visual measures both before and after surgery.

REFRACTIVE IMPLANTS GUIDANCE DEVELOPMENT

The Panel was asked to address issues related to the development of the clinical studies section of the guidance. The discussion topics are listed below.

Scope of the Document

  • FDA had not previously discussed clear lens exchange with the Panel. However, these procedures are being done off-label and it has become important to furnish guidance to companies wishing to pursue this indication. FDA sought the Panel’s recommendations for the proposed guidance document.
  • The Panel debated whether to include clear lensectomy (clear lens exchange) in the Refractive Implants guidance document. They agreed that the evaluation of refractive implants and clear lens exchange is essentially the same, but the risk/benefit ratio and possible rates of adverse events are different and should be taken into account in the study design.
  • Then the panel expressed their concern regarding the potential loss of accommodation and the increased risk of retinal detachments with the refractive implant particularly for those patients with greater degrees of myopia.
  • They discussed the following with respect to the studies for clear lens exchange:
  • Age inclusion criteria
  • Safety endpoints should be the same as Refractive Implant studies
  • Concurrent controls or historical population as a control
  • Degree of myopia studies – lower limits (-11 Diopters or less)
  • Hyperopia studied – not less than +5.00 Diopters
  • Studies to include a required subset for visual fields evaluation
  • The use of control subjects when evaluating IOLs for clear lens exchange.

Endothelial Cell Counts

  • The Panel agreed with the FDA that a maximum rate of surgical loss of 10% was reasonable for the studies.
  • The Panel agreed with the FDA that a sample size of 200 subjects would allow the detection of a rate of chronic loss great than 1.5% per year.
  • The analysis of the endothelial cell counts should be stratified by the age of the patients.
  • They agreed with the FDA that the analyses of endothelial cell loss should include the mean rate of cell loss over time, calculated via a paired analysis in order to calculate the mean of the differences, and a frequency analysis examining the percentage of patients who lose greater than 10% of cells between Month 3(or Month 6) and Month 36.

Cataractogenesis

  • The panel recommended the use of controls most particularly in the area of cataract formation/changes to the natural lens that may occur from the presence of a refractive implant. Since the rate of natural cataract formation in younger patients (less than 60 years of age) is not very well known, the Panel members recommended the use of age-matched controls.
  • The Panel suggested that the Beaver Dam Eye Study system be added to the LOCS III and Oxford grading systems for evaluation of the cataract both preoperatively and at each visit postoperatively. The Panel also recommended that the FDA look into wavefront aberrations testing for future studies.
  • To avoid the confounding variable of age-related cataracts, the Panel recommended that there be separate studies for younger and older patients.
  • Younger patients would include the 20-30 age group. They also recommended stratifying results by age decade.

Closing Comments

The Panel meeting tentatively scheduled for July 27-28, 2000 has been cancelled. 

Contact: Sara M. Thornton, Executive Secretary
(301) 594-2053, ext.127; e-mail smt@cdrh.fda.gov

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EXECUTIVE SUMMARY MAY BE PURCHASED FROM:
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Food and Drug Administration
Freedom of Information Staff (FOI)
5600 Fishers Lane, HFI-35
Rockville, MD 20852
(301) 827-6500 (voice) (301) 443-1726 (fax)