# Presentation: 707500

## Discussion of a Post-Marketing Approval Study for 30-day Continuous Wear Contact Lenses

**Notes:**
In the early 1980s, the FDA approved some contact lenses for up to 30 days of continuous wear. 
Increasing reports of problems with corneal ulcers prompted investigation of extended wear safety that culminated in the studies of Schein et al  and Poggio et al . 
Results from these studies prompted the FDA to recommend that continuous wear be limited to a maximum of 7 days.

## Gene Hilmantel, O.D., M.S.

**Gene Hilmantel, O.D., M.S.**
**Bernard P. Lepri, O.D., M.S., M.Ed.**
**James F. Saviola, O.D.**
**Rosalie A. Bright, Ph.D.(****OSB/DPS****)**

## New contact lens materials with much higher oxygen transmission may have the potential for safer continuous wear for longer periods of time.

**Notes:**
There are now about 33 million nationwide. About 15% are EW (maybe 4 - 5 million?) Only about 10 to 15 percent of patients routinely use their lenses for extended wear, though perhaps twice this percentage occasionally sleep with their lenses on. 

## The incidence of corneal ulcers is the main concern. 

**The incidence of corneal ulcers is the main concern. **

**Notes:**
maybe 3 million patients sleep in lenses regularly.
 In a given year maybe (.002)*3,000,000 = 6,000 have an ulcer. 
Maybe another 6 - 9,000 DW soft wearers have ulcers. About half of all ulcers are Cl related.
Risk of corneal infection among CL wearers compared to non-wearers is (40-) 80x. (Dart)

## Although a serious problem, the incidence of ulcers is too low to reliably determine the risk in a reasonable PMA study.

**Notes:**
400-800 subjects in study. 6-12 months

## The FDA’s position is that the best way to address this concern is to require a “Post-Marketing Approval Study” of the risk posed by 30-day “continuous wear.” 

## What is an unacceptable ulcer rate? 

**Notes:**
.Risk of corneal infection among CL wearers compared to non-wearers is (40-) 80x. (Dart)

## Relative Risk

**Relative Risk**
**(Risk of EW ulcer/Risk of DW ulcer)**

- from Schein O, et al. The relative risk of ulcerative keratitis among users of daily-wear and extended-wear soft contact lenses. New Eng J Med 1989;321:773-778

- (continuous wear)

**Notes:**
Schein’s findings (from a case-control study) indicated that :
the risk of ulcerative keratitis for patients who slept in their extended-wear lenses was 10 -15 times that of those in strictly daily-wear, and
the risk increased with each additional day of extended wear.

Hygiene practices relatively unimportant as risk factors.
Defn: ulcerative keratitis: corneal epithelial defect with underlying stromal infiltrate, cultured and treated with antibiotics.
Schein Arch Ophth 1994;112:186-190. 8.25 RR

## From the 1989 Schein data, it seems that a “relative risk” of about 12-15 (compared to Daily Wear) was considered unacceptable.

## Poggio’s 1989 study* found that the incidence of ulcers was: 

**4 per 10,000** in DW patients,
**20 per 10,000** in EW patients.

- *Poggio EC, et al. The incidence of ulcerative keratitis among users of daily-wear and extended-wear soft contact lenses. New Eng J Med 1989;321:779-783

**Notes:**
A  survey of all ophthalmologists in a five state area for a period of 4 months.
 In a five state area (population 8,000,000 12 years or older) there were a total of 128 (48 DW, 80 EW) cases of cosmetic CL ulcer (195 total CL ulcer cases).

Of the total population of appropriate age, about 4 - 5 % wore DW, about 1 - 2 % wore EW. But about 38% of EW wearers wore lenses only as DW. He found 20/10,000 for EW, 4/10,000 for DW.  At the time there were about 18 million CL wearers. 9 million DW, 4 million EW (22% of all CLs, or almost half of the number of DWs).
2-3 / 10,000 estimated in strictly DW
22-32/10,000 estimated for strictly EW.

Nilsson SE; Montan PG . CLAO J, 1994 Oct, 20:4, 225-30 :Incidence in Sweden (2per DW, 10per EW)about half the incidence of US.

## Assuming that 15x the risk of daily wear is unacceptable, this means that :

**15x(4/10,000) = 60/10,000 is too much risk.**
**60/10,000** is about **2 - 4 times** the risk of 7-day Extended Wear.

## Number of Years Wearing Contacts

**Lifetime ulcer risk** Vs **Number of Years Wearing Contacts**

**Number of Years Wearing Contacts**

**Lifetime ulcer risk**

## Question: 

**Question: **
**Does the panel feel that using 60/10,000 ulcers/patient-year (about 3x the 7-day EW rate) as an upper limit is reasonable?**

## What Type of Study 

**What Type of Study **
**Should Be Recommended?**

- Incidence

- Relative Risk

**Case-Control**
**Study**

**Follow**
**Cohort**

## Advantages of a Case-Control Study:

**Good for the study of rare diseases.**
**Relatively inexpensive.**
**Can assess relative risk of different hygiene practices.**
**“****Real World” environment. Patients and practitioners NOT self or other selected.**

**Advantages of a Case-Control Study:**

## Disadvantages of a Case-Control study:

**Only assesses relative risk, not actual incidence of ulcers. Ulcer rate for 7-day lenses may have decreased since 1989 (since 30-day wear was eliminated).**
**Generally produces large confidence intervals, or else need very large number of ulcers. E.g., in Schein(1989):  RR of overnight EW to DW was 10.2, with a CI of 5.3 - 19.6.**** **

**Disadvantages of a Case-Control study:**

## Question: Will there be difficulty in getting enough EW ulcer cases?

- Schein (1989) had 86 in study (52 were EW).
- Half of all CL-related ulcers are DW.
- Change in pattern of care for ulcers since 1980s.

**Notes:**
In the late 1980s, virtually all ulcers were seen by ophthalmologists, many of them by corneal specialists. Today, many are treated by optometrists, and the availability of ciprofloxacin and ofloxacin mean that fewer are referred to sub-specialists. Schein’s 1989 study had only 86 ulcer patients (34 DW and 52 EW), or about 14 from each of six centers.
In the late 1980s, virtually all ulcers were seen by ophthalmologists, many of them by corneal specialists. Today, many are treated by therapeutic optometrists, and the availability of ciprofloxacin and ofloxacin mean that fewer are referred to sub-specialists.

in Schein ‘89 study: 6 University centers, ~100 ulcer patients from 6 University  ophthalmologic centers over a period of one year. (~16/center). Of these, about 85% completed the interview. 34 (40% were DW and 52(60%) were EW.
.30 percent and 66 percent of cases of ulcerative keratitis seen in major eye centers are contact lens related.292 ulcers in a 9 year period at Bascom–Palmer (not just CL related). I.e maybe 20/year CL-related in a large eye center. Thus it’s probably unrealistic to collect more than 120-360 ulcers in a multi-center (6) study. Of these, maybe 60-180 would be EW.

## Cases ( EW Ulcers) Required for 80% Power to Detect Relative Risk*

- *Table is for testing H0: Relative Risk= 1. (30-Day/7-Day Wear)
- ONE-SIDED TEST, =.05.

**Cases ( EW Ulcers) Required for 80% Power to Detect Relative Risk***

- Relationship between Sensitivity of test and required Sample Size.

**Notes:**
Alternate Hypothesis Relative Risk is a measure of test sensitivity to departures from the null hypothesis: RR=1.

## Statistical POWER is a key measure of our confidence in product safety.

**Power and sample size are strongly related.**

**Cases (Ulcers) Required to Detect Relative Risk***

- *Table is for testing H0: Relative Risk= 1. (30-Day/7-Day Wear)
- ONE-SIDED TEST, =.05.

## There is an interplay between Market Penetration and Sensitivity & Power of the  test.

- Table is for testing H0: Relative Risk= 1. **ONE-SIDED TEST**, =.05

**Cases (Ulcers) Required for ****90%**** Power to Detect Relative Risk***

## Questions: 

**What statistical POWER  would the panel recommend to ensure confidence in the result?**
**Should we wait for greater penetration of the market, in order to achieve greater sensitivity and power?**

## Following a cohort of 30-day wearers  is an alternative way to assess risk.

**Could be done by requiring a large number of practitioners to fill out a small follow-up questionnaire after 1 year of experience with the lens.**

## Disadvantages of a Cohort study:

**Selected patients.**
**Selected practitioners.**
**Relatively controlled follow-up environment.**
**Cost?**

**Advantages of a Cohort Study:**

**May yield results within ~ 2 years(?) of ****	****	****FDA approval.**
**Can assess incidence of ulcers.**
**May assess incidence of other complications.**

## Significant increases in ulcer rate are detectable with a large sample size. (Here, Testing the null hypothesis: ulcer rate  0.0020)*

- *For **ONE-SIDED TEST**; alpha=0.05

- Significant increases in ulcer rate are detectable with a large sample size. (Here, Testing the null hypothesis: ulcer rate  0.0020)*

**Notes:**
Numeric Results when H0: P0 = P1 versus Ha: P0<P1.				

Power	N	P0	P1	
0.95	2824	0.002	0.006	
0.90	2164	0.002	0.006	
0.80	1512	0.002	0.006	

## private practitioners

- commercial chains
- HMOs
- all of the above
- sponsor’s discretion

## Would the panel recommend:

**a case-control study?**
**following a large cohort?**
**both?**

## Question: How would the panel define the endpoints that we are interested in for the study?

**Endpoints used could be: **
**Patients with presumed infectious ulcers;**
**Patients with any type of ulcers;**
**Patients with central or para-central scars (not present at pre-fit);**
**Patients with reduction in acuity associated with scaring;**
**Other?**

## Questions?

**Comments?**