Example of What a CR Letter Looks Like
LaJolla CR from a few years back (source: SEC Edgar).
EXHIBIT 99.2
[United States Food and Drug Administration Letterhead]
La Jolla Pharmaceutical Company
Attention: Lisa I. Koch
6455 Nancy Ridge Drive
San Diego, CA 92121
Dear Ms. Koch:
Please refer to your new drug application (NDA) dated December 14, 2003,
received December 16, 2003, submitted under section 505(b) of the Federal Food,
Drug, and Cosmetic Act for Riquent (abetimus sodium) 50 mg/ml Injection.
We acknowledge receipt of your submissions dated December 14, 2003 and January
8, 22, February 6, March 2, 15 (two), 19, 24, 30, April 2, 5 (two), 9, 13 (two),
15, 28, May 28, June 8, 11, 15, 17, 24 (two), 25, 29, 30, July 6, 13, 20, 21
(two), 22, August 2, 4 (two), 11 (two), 12, 13, 18, 19 (two), 20 (three), 31,
(two), September 9, 10, 27, and October 1, 2004.
We have completed our review of this application, as amended, and it is
approvable. Before the application may be approved, however, it will be
necessary for you to address the following concerns:
Your study 90-05 was designed to show a clinical benefit (delayed time to
renal flare) associated with treatment, but it failed to do so. An unplanned
analysis of patients with high affinity antibodies to dsDNA appeared to show
benefit, leading to study 90-09, designed to study benefit in that high
affinity subgroup. Study 90-09 also failed to show benefit, thus failing to
support the hypothesis raised by the subgroup analysis in study 90-05.
Whether these results indicate that the hypothesis that lowering anti-dsDNA
antibodies slows disease progression is wrong or that the effect was too
small to affect disease progression cannot yet be known. Only another, better
powered outcome trial, perhaps with a larger dose, will resolve this issue.
The combined analysis of the high affinity subgroup of study 90-05 and study
90-09 is not a credible analysis as it is driven by the retrospective
analysis of study 90-05.
To gain approval, you will need to conduct a further randomized, double-blind
study that successfully distinguishes abetimus from placebo on an endpoint of
clinical benefit, such as time to renal flare. Your ongoing clinical study
(90-14) would appear to satisfy this requirement, although we think that it
could be valuable to learn more about the dose-response for the effect of
abetimus on antibody titer before carrying out a large clinical trial of long
duration.
Because a description of the drug's effects and proper use are yet to be
determined, at this time, we are deferring comments on labeling.
In addition, we have the following request:
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We remind you that before we can establish a definitive expiration dating
period for the drug product, you should develop a more sensitive stability
indicating analytical method for the drug product.
Within 10 days after the date of this letter, you are required to amend this
application, notify us of your intent to file an amendment, or follow one of
your other options under 21 CFR 314.110. If you do not follow one of these
options, we will consider your lack of response a request to withdraw the
application under 21 CFR 314.65. Any amendment should respond to all the
deficiencies listed. We will not process a partial reply as a major amendment
nor will the review clock be reactivated until all deficiencies have been
addressed.
Under 21 CFR 314.102(d), you may request an informal meeting or telephone
conference with this division, the Division of Cardio-Renal Drug Products, to
discuss what steps need to be taken before the application may be approved.
The drug product may not be legally marketed until you have been notified in
writing that this application is approved.
If you have questions, please contact:
Dianne C. Paraoan
Regulatory Health Project Manager
(301) 594-5308
Sincerely,
/s/ Robert Temple, M.D.
Robert Temple, M.D.
Director
Office of Drug Evaluation I
Center for Drug Evaluation and Research
