Discussion of a PostMarketing Approval Study for 30day Continuous Wear Contact Lenses

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Discussion of a Post-Marketing Approval Study for
30-day Continuous Wear Contact Lenses
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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)
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New contact lens materials with much higher
oxygen transmission may have the potential for
safer continuous wear for longer periods of time.
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The incidence of corneal ulcers is the main
concern.
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Although a serious problem, the incidence of
ulcers is too low to reliably determine the risk
in a reasonable PMA study.
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The 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.
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What is an unacceptable ulcer rate?
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Relative 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
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From the 1989 Schein data, it seems that a
relative risk of about 12-15 (compared to Daily
Wear) was considered unacceptable.
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• 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
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• 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.

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Lifetime ulcer risk Vs Number of Years Wearing
Contacts
Lifetime ulcer risk
Number of Years Wearing Contacts
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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?
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What Type of Study Should Be Recommended?
Incidence
Relative Risk
Case-Control Study
Follow Cohort
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Advantages 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.

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Disadvantages 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.

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• 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.

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Relationship 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.
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• 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.
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There 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
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• 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?

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• 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.

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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.

Disadvantages of a Cohort study

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

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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 alpha0.05
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• 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

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• Would the panel recommend
• a case-control study?
• following a large cohort?
• both?

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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?

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• Questions?
• Comments?