Title: Discussion of a PostMarketing Approval Study for 30day Continuous Wear Contact Lenses
1Discussion of a Post-Marketing Approval Study for
30-day Continuous Wear Contact Lenses
2Gene 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)
3New contact lens materials with much higher
oxygen transmission may have the potential for
safer continuous wear for longer periods of time.
4The incidence of corneal ulcers is the main
concern.
5Although a serious problem, the incidence of
ulcers is too low to reliably determine the risk
in a reasonable PMA study.
6The FDAs 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.
7What is an unacceptable ulcer rate?
8Relative Risk (Risk of EW ulcer/Risk of DW ulcer)
(continuous wear)
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 1989321773-778
9From the 1989 Schein data, it seems that a
relative risk of about 12-15 (compared to Daily
Wear) was considered unacceptable.
10- Poggios 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
1989321779-783
11- 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.
12Lifetime ulcer risk Vs Number of Years Wearing
Contacts
Lifetime ulcer risk
Number of Years Wearing Contacts
13Question 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?
14 What Type of Study Should Be Recommended?
Incidence
Relative Risk
Case-Control Study
Follow Cohort
15Advantages of a Case-Control Study
- Can assess relative risk of different actual
wearing schedules. - 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.
16Disadvantages of a Case-Control study
- Requires a waiting period (3 - 5 years?), until
30-day lenses have sufficient market share. - 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.
17- 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.
18Relationship between Sensitivity of test and
required Sample Size.
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.
19- 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.
20There is an interplay between Market Penetration
and Sensitivity Power of the test.
Cases (Ulcers) Required for 90 Power to Detect
Relative Risk
Table is for testing H0 Relative Risk 1.
ONE-SIDED TEST, ?.05
21- 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?
22- 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.
23Advantages of a Cohort Study
- May yield results within 2 years(?) of FDA
approval. - Can assess incidence of ulcers.
- May assess incidence of other complications.
Disadvantages of a Cohort study
- Selected patients.
- Selected practitioners.
- Relatively controlled follow-up environment.
- Cost?
24Significant increases in ulcer rate are
detectable with a large sample size. (Here,
Testing the null hypothesis ulcer rate ? 0.0020)
For ONE-SIDED TEST alpha0.05
25- Question What type of clinical setting does the
panel recommend for implementation of a
post-approval study? - private practitioners
- commercial chains
- HMOs
- all of the above
- sponsors discretion
26- Would the panel recommend
- a case-control study?
- following a large cohort?
- both?
27Question 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?
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