[Federal Register Volume 62, Number 64 (Thursday, April 3, 1997)]
[Notices]
[Pages 15903-15914]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-8517]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
[Docket No. 94N-0171]
Discovery Experimental and Development, Inc.; Denial of a Hearing
and Refusal to Approve a New Drug Application for Deprenyl (Deprenyl
Citrate) Gelatin Capsules and Liquid; Final Order
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Commissioner of Food and Drugs (the Commissioner) is
denying a request for a hearing and is issuing an order under the
Federal Food, Drug, and Cosmetic Act (the act) refusing to approve a
new drug application (NDA) for Deprenyl (deprenyl citrate) submitted by
Discovery Experimental and Development, Inc., 29949 S.R. 54 West,
Wesley Chapel, FL 33543 (Discovery). Discovery requested an opportunity
for a hearing after the Food and Drug Administration (FDA) issued a
proposal to refuse to approve the firm's NDA for Deprenyl. FDA is
denying Discovery's request for a hearing because Discovery failed to
raise any genuine and substantial issue of fact that would entitle it
to such a hearing. FDA bases this order refusing to approve Discovery's
product on a finding that, among other deficiencies in the application,
there is insufficient information to determine whether Discovery's
deprenyl citrate is safe for use or will have the effect it purports or
is represented to have under the conditions of use prescribed,
recommended, or suggested in the proposed labeling.
EFFECTIVE DATE: April 3, 1997.
[[Page 15904]]
FOR FURTHER INFORMATION CONTACT: Brian J. Malkin, Office of Health
Affairs (HFY-40), Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857, 301-827-1698.
SUPPLEMENTARY INFORMATION:
I. Background
On November 29, 1991, Discovery submitted NDA 20-242 for deprenyl
citrate (also referred to in Discovery's response to the notice of
opportunity for a hearing (NOOH) as deprenyl and selegiline), proposing
to label it for the treatment of Alzheimer's disease.\1\ On December 7,
1992, Discovery submitted an amendment to the NDA.
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\1\ An NDA for another deprenyl product, selegiline
hydrochloride (Eldepryl), was approved by FDA on June 5,
1989, for the treatment of Parkinson's disease. The NDA is held by
Somerset Pharmaceuticals, Inc., Tampa, FL (hereinafter referred to
as Somerset).
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In a letter dated January 17, 1992, FDA notified Discovery that it
was not filing NDA 20-242, under Sec. 314.101(d) (21 CFR 314.101(d)),
because the application did not contain information necessary to permit
a substantive review. In the letter, FDA listed the reasons for its
refusal as required by Sec. 314.101. In its reply letter dated January
23, 1992, Discovery requested an informal conference with FDA.
Following subsequent communications with Discovery regarding the
scheduling of the hearing,\2\ the conference was held on November 16,
1992.
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\2\ Subsequent communication occurred in letters dated: March 4,
1992; March 17, 1992; March 19, 1992; August 26, 1992; September 16,
1992; September 21, 1992; September 23, 1992; October 8, 1992;
October 9, 1992; October 13, 1992; October 20, 1992; and October 28,
1992.
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At the conference, FDA informed Discovery of its (Discovery's)
options in light of FDA's refusal to file the NDA. In a letter dated
November 24, 1992, FDA reiterated that Discovery's application could be
filed over protest under Sec. 314.101(c),\3\ which Discovery requested
on December 7, 1992.
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\3\ Now codified in Sec. 314.101(a)(3).
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In a letter dated December 31, 1992, FDA notified Discovery that
FDA would file the NDA over protest; that the application would be
reviewed ``as filed;'' that, in accordance with Sec. 314.101(c), any
amendment received after December 10, 1992, would not be considered;
and that FDA considered Discovery's December 7, 1992, amendment, to be
a ``major amendment'' within the meaning of Sec. 314.60(a) (21 CFR
314.60(a)), requiring 180 days for its review.
In a letter dated August 20, 1993, and in accordance with
Sec. 314.120 (21 CFR 314.120), FDA advised Discovery that NDA 20-242
was not approvable. In the letter, FDA explained in detail the reasons
for its judgment. Discovery responded by letter dated September 1,
1993, and, under Sec. 314.120(a)(5), requested an extension of 180 days
to consider its options with respect to the NDA. FDA granted the
extension. In a letter dated March 1, 1994, Discovery requested an
opportunity for a hearing under Sec. 314.120(a)(3) on the question of
whether there were grounds for FDA's refusal to approve NDA 20-242.
In the NOOH of May 19, 1994, FDA proposed to refuse to approve
Discovery's NDA and offered Discovery an opportunity for a hearing.
FDA's NOOH informed Discovery that if it requested a hearing, it could
not rest on mere allegations or denials but would have to present
specific facts showing that there was a genuine and substantial issue
of fact requiring a hearing. The NOOH also stated that if it
conclusively appeared from the face of the data, information, and
factual analysis submitted in support of a hearing request that there
was no genuine and substantial issue of fact precluding the refusal to
approve the NDA, or if the request for a hearing was not made in the
required format with the required analyses, the Commissioner would
enter summary judgment against Discovery, denying its request for a
hearing. In a letter filed on June 14, 1994, Discovery submitted a
request for a hearing and supporting arguments (Discovery's
response).\4\
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\4\ On p. 1 of its response, Discovery stated that it was
addressing its NADA's 20-242 and 20-244. However, as stated by
Discovery on pp. 4 and 5 of its response, it had not yet filed NDA
20-244. The NOOH pertained only to NDA 20-242.
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I have reviewed Discovery's arguments and find that Discovery has
not raised a genuine and substantial issue of fact requiring a hearing
under Secs. 12.24(b) and 314.200(g) (21 CFR 12.24(b) and 314.200(g)),
and that summary judgment should be granted against Discovery.
Moreover, on the basis of all, or any one of, the numerous deficiencies
in Discovery's NDA, I find that I cannot approve NDA 20-242, under
section 505(d) of the act (21 U.S.C. 355(d)). The reasons for my
decision are described below.
II. Discovery's Response to the NOOH
A. Discovery's General Allegations
Before responding to the specific deficiencies in NDA 20-242 cited
by FDA in the NOOH, Discovery made numerous preliminary allegations and
accusations against FDA in its request for a hearing.\5\ Generally,
Discovery alleged that FDA was biased, misused its power, and violated
numerous regulatory requirements, as well as Discovery's constitutional
rights, during its review of NDA 20-242. In sections II.A.1 through
II.A.3 of this document, I address allegations that Discovery made on
pp. 2-26 of its response, all of which in some way challenge the
statutory or regulatory requirements for the approval of new drugs. In
section II.A.4 of this document, I address Discovery's allegations of
agency bias and incompetency with respect to FDA's review of NDA 20-
242, contained in pp. 18-20 of its response. In section II.A.5 of this
document, I address 13 specific ``illegalities'' that Discovery alleged
were committed by FDA, and which are listed on pp. 27-29 of Discovery's
response.
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\5\ In its response, Discovery refers to itself by its acronym,
DEDI.
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1. FDA has misused its power as a government agency by enforcing
its regulations ``as if they were laws enacted by Congress.''
Discovery's allegation is a legal argument that does not raise a
genuine and substantial issue of fact requiring a hearing
(Secs. 12.24(b)(1) and 314.200(g)). Regulations issued under the act
and under the notice and comment provisions of the Administrative
Procedures Act (5 U.S.C. 553) have the force and effect of law. It is
appropriate for FDA to enforce them as having such effect (Weinberger
v. Hynson, Westcott & Dunning, Inc., 412 U.S. 609 (1973); National
Ass'n of Pharmaceutical Mfrs. v. FDA, 487 F. Supp. 412 (S.D.N.Y. 1980),
aff'd, 637 F.2d 877 (2d Cir. 1981)). Therefore, there is no misuse of
power by FDA, and there is no merit to Discovery's allegation.
2. ``The Commissioner has the power to approve or disapprove any
pharmaceutical, without conducting any trials, or without following any
regulations, simply with the stroke of a pen.''
The first part of Discovery's allegation, that FDA can approve or
disapprove a new drug without it conducting any trials, is true. The
act places the burden of conducting the trials required for the
approval of a new drug on the applicant, not FDA (section 505(b) of the
act). However, this fact has no probative value in the case. It only
raises the question whether the necessary trials have been done.
As to the second part of Discovery's assertion, that the
Commissioner does not have to follow any regulations, while the
Commissioner has the authority to use discretion in the enforcement of
the act and its implementing regulations, and while certain criteria
that apply to clinical investigations may be waived (e.g.,
Sec. 314.126(c) (21 CFR 314.126(c))), the
[[Page 15905]]
Commissioner may not disregard the statutory standards for the approval
of new drugs (section 505(d) of the act (requiring that the
Commissioner shall issue an order refusing to approve an NDA if he
finds certain information lacking) (emphasis added); Edison
Pharmaceutical Co., Inc. v. FDA, 600 F.2d 831 (D.C. Cir. 1979);
Hoffman-LaRoche, Inc. v. Weinberger, 425 F. Supp. 890 (D.D.C. 1975);
see also, Sec. 314.200(e)(3)). New drugs are to be approved on the
basis of substantial evidence consisting of adequate and well-
controlled investigations, including clinical investigations (section
505(b) of the act). Indeed, FDA's new drug approval process has been
upheld by the Supreme Court as a constitutional means of protecting the
public from unsafe or ineffective drugs (Weinberger v. Hynson, Westcott
& Dunning, Inc., 412 U.S. 609 (1973)). Discovery's response, therefore,
is not correct as a matter of law. It does not present an issue of fact
for resolution at a hearing, Secs. 12.24(b)(1) and 314.200(g), and is
without merit.
3. ``FDA requires a drug to be tested in a multitude of phases with
the most absurd required testing being the double blind, placebo based
clinical trial,'' and that this requirement is unconstitutional.
The act requires an applicant to submit substantial evidence of
safety and effectiveness and defines substantial as consisting of well-
controlled studies (section 505(b) and (d) of the act). FDA regulations
in turn identify the characteristics of a well-controlled study,
advising applicants that one hallmark of a well-controlled study is the
use of procedures to minimize bias, such as blinding and use of
placebos (Sec. 314.126). Discovery's allegations, therefore, challenge
the statutory and regulatory requirements of the act for the approval
of a new drug. As such, they are legal arguments, which do not raise an
issue of fact requiring a hearing (Secs. 12.24(b)(1) and 314.200(g)).
Nor do these arguments have any merit. FDA's testing requirements have
been specifically upheld by the Supreme Court (Weinberger v. Hynson,
Westcott, & Dunning, supra).
4. FDA is arrogant, incompetent, and biased; and has conspired with
the drug industry and the American Medical Association to target
nonmainstream practitioners in order to eliminate the competition with
certain pharmaceutical companies.
Discovery did not submit any specific evidence that FDA failed to
perform a competent review of NDA 20-242, or that it conspired with the
American Medical Association to eliminate competition in the drug
industry by disapproving NDA 20-242. Similarly, Discovery did not
submit any specific and reliable evidence of arrogance or bias in FDA's
review of NDA 20-242. Because Discovery's response consists of mere
allegations, it fails to raise a genuine and substantial issue of fact
requiring a hearing (Secs. 12.24 (b)(2) and 314.200(g)). I find that
the record reflects that, in FDA's review of Discovery's NDA, it was
appropriately concerned with one primary issue--whether NDA 20-242
contained the information required by the act. Therefore, I find no
merit to Discovery's allegation.
5. FDA has committed 13 ``illegalities,'' as follows (Discovery
response, pp. 27-29):
a. FDA violated Discovery's Fourth Amendment rights under the
Constitution by illegally searching and seizing all items relating to
Deprenyl in December 1990, which led to the illegal arrest and
incarceration of Discovery's president in February 1991.
Discovery's allegation that FDA violated Discovery's constitutional
rights are legal arguments, which do not raise a genuine and
substantial factual issue of fact for which a hearing is required
(Secs. 12.24(b)(1) and 314.200(g)).
Moreover, in support of this allegation, Discovery submitted
exhibit 2, attached to its response. Exhibit 2 consists of photocopies
of an Order On Defendant's Motion To Suppress and an Order Dismissing
Case and Releasing Cash Bond (Case No. 91-622CFAES). It is facially
apparent that these documents pertain to a matter within the
jurisdiction of the Criminal Division of the Circuit Court for Pasco
County, FL, namely a vehicular stop for a traffic violation and
subsequent seizure of unidentified pills and powder by the Pasco County
Sheriff's Office from the possession of Mr. James Kimball, President of
Discovery, on December 21, 1990.\6\ Discovery's exhibit in support of
its allegation does not indicate any FDA involvement in the traffic
stop and seizure.\7\ An alleged violation of Mr. Kimball's or
Discovery's constitutional rights involving a traffic stop and seizure
by a Pasco County, FL, sheriff's office does not raise a genuine issue
of fact related to the approvability of NDA 20-242 requiring a hearing
(Secs. 12.24(b)(1) and 314.200(g)). The allegation simply is not
relevant to this proceeding.
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\6\ Even if this allegation were true, it is difficult to see
its relevance given the fact that it occurred before Discovery
submitted its NDA to FDA (November 1991).
\7\ Discovery also contends on p. 2 of its response that FDA
violated it's First Amendment right to free speech when FDA
``instigated'' the illegal stop, search, and seizure.
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b. FDA deliberately misconstrued applications Discovery submitted
to have its products approved and returned them to the company.
Discovery submitted the applications to which it refers in an
unsuccessful effort to have its product regulated as a food supplement
rather than as a new drug. See letter dated April 10, 1991, from FDA to
Discovery submitted in Discovery's NOOH response as exhibit 3. As the
letter states, the applications were returned to Discovery because the
product could not be regulated as a food supplement as requested by
Discovery. Discovery's statement regarding the return of its
applications, therefore, is true. Discovery did not submit any
evidence, however, in support of its allegation that FDA ``deliberately
misconstrued'' its applications.
To the extent that Discovery alleges that FDA returned its
applications, there is no question but the allegation is true. To the
extent that Discovery alleges that FDA ``deliberately misconstrued''
its applications, however, Discovery's response consists of a mere
allegation. Mere allegations do not raise a genuine and substantial
issue of fact requiring a hearing (Secs. 12.24(b)(2) and 314.200(g)).
There is nothing in the record that indicates that FDA
``deliberately misconstrued'' Discovery's request that FDA regulate
Deprenyl as a food supplement, or that FDA's return of the applications
was improper. The letter from FDA to Discovery explains why FDA could
not regulate Deprenyl as a food supplement. In its response, Discovery
did not challenge the basis of FDA's decision in its response. Finally,
Discovery was not hindered in any way from resubmitting the
applications as NDA's. Therefore, Discovery's allegation has no
probative value in, and is not relevant to, this proceeding.
c. FDA lost two applications that Discovery submitted in April 1991
for Liquid Deprenyl Citrate.
Irrespective of the validity of Discovery's allegation, FDA's
action with respect to other NDA's is not determinative of the
approvability of NDA 20-242. The matter before me pertains to FDA's
proposal to refuse to approve NDA 20-242 due to insufficient
information contained in the NDA, not to alleged FDA actions pertaining
to other NDA's.
In addition, in light of other serious deficiencies associated with
NDA 20-242, resolution of this issue is not determinative with respect
to the approvability of NDA 20-242. At most, Discovery's response
raises an issue for
[[Page 15906]]
which a hearing is not required (Secs. 12.24(b)(4) and 314.200(g)).
d. FDA violated Sec. 314.103 (21 CFR 314.103) in January 1992 by
not granting a hearing to Discovery regarding its two NDA's for Liquid
Deprenyl Citrate.
Section 314.103 expresses FDA's policy in favor of the timely and
amicable resolution of disputes between an applicant and FDA reviewing
divisions regarding the technical requirements of NDA's. It also
advises applicants to seek the assistance of the agency ombudsperson to
resolve such difficulties. Section 314.103(c)(2) states that, ``FDA
will make every attempt to grant requests for meetings that involve
important issues and that can be scheduled at mutually convenient
times.''
Discovery requested a meeting with FDA officials in a letter that
FDA received on January 29, 1992. Thereafter, the record reflects
numerous communications between the agency and Discovery\8\ during
which Discovery sought the assistance of FDA's ombudsperson in
scheduling a meeting. Agency officials met with Discovery on November
16, 1992. Assuming that Discovery's allegation is that FDA officials
violated Sec. 314.103 because they failed to meet with Discovery in
January 1992, but instead delayed until November 1992, the regulations
placed no burden on FDA to meet with Discovery within any specific time
period other than ``at [a] mutually convenient'' time. Therefore, I
find that the information submitted by Discovery is insufficient to
justify Discovery's allegation that FDA ``violated'' Sec. 314.103 in
January 1992. A hearing, therefore, is not required (Secs. 12.24(b)(3)
and 314.200(g)).
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\8\ Supra note 2.
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Furthermore, even if Discovery's allegation is viewed as accurate,
in light of the numerous serious deficiencies in NDA 20-242, resolution
of this issue would not be determinative of the basic issue in this
matter, the approvability of the NDA, and a hearing, therefore, is not
required (Secs. 12.24(b)(4) and 314.200(g)).
e. FDA violated Sec. 314.102(c) (21 CFR 314.102(c)) by not granting
Discovery a ``90-day conference.''
Discovery's contention is that FDA failed to grant a conference
within 90 days after receiving Discovery's NDA. This statement is true.
The purpose of a ``90-day conference'' is ``to provide applicants with
an opportunity to meet with agency reviewing officials [approximately
90 days after FDA receives an NDA] * * * to inform applicants of the
general progress and status of their applications, and to advise
applicants of deficiencies that have been identified by that time and
that have not already been communicated'' (Sec. 314.102(c) (emphasis
added)).
FDA received NDA 20-242 on November 29, 1991, and an amendment to
the NDA on December 6, 1991. On January 17, 1992, FDA notified
Discovery of the deficiencies in its application, and that it was
refusing to file NDA 20-242. Although there is no question that FDA did
not offer Discovery a conference on any deficiencies that it had not
communicated, its failure to do so does not justify a hearing. A 90-day
conference with Discovery would have served no purpose. When Discovery
filed its application over protest, FDA had already informed Discovery
that NDA 20-242 did not contain information required by section 505(b)
of the act and Sec. 314.101(d)(3). There was no question about the
status of the application or any noncommunicated deficiencies.
Therefore, there was no new information to convey to Discovery in a 90-
day conference.
I find that Discovery was not prejudiced in any way by FDA's
failure to grant it a 90-day conference. Moreover, in light of the
other significant deficiencies in NDA 20-242, the issue of whether FDA
should have done so is not determinative of whether the NDA is
approvable. This allegation by Discovery, therefore, does not raise a
factual issue on which a hearing is required (Secs. 12.24(b)(4) and
314.200(g); also see Pineapple Growers Assoc. of Hawaii v. Food and
Drug Administration, 673 F.2d 1083, 1086 (9th Cir. 1982)).
f. FDA violated Discovery's constitutional rights under the Fifth
and Fourteenth Amendments by ``making up'' rules regarding amendments
to Discovery's application during final review.
Discovery's allegation that FDA violated Discovery's constitutional
rights are legal arguments and, as such, fail to raise a genuine and
substantial factual issue for which a hearing is required
(Secs. 12.24(b)(1) and 314.200(g)).
Upon review of the record, I find no evidence that FDA ``made up''
rules regarding the submission of amendments to NDA's filed over
protest. The record reflects that FDA informed Discovery in a letter
dated November 24, 1992, that after an NDA is filed over protest, FDA
would not consider additional amendments in the review of the NDA, in
accord with Sec. 314.101(c) (now Sec. 314.101(a)(3)). This regulation
states that, ``the agency will file the application * * * over protest
* * * and review it as filed'' (emphasis added). Further, in the
November 24, 1992, letter, FDA responded to Discovery's suggestion that
it might want to summit an amendment to its NDA and advised Discovery
that it could amend its application so long as it did so before it was
filed over protest. Discovery was, thus, fully advised of the
regulatory requirements regarding the submission of amendments to its
NDA filed over protest.
g. FDA violated Secs. 314.102(a) and (b) and 314.103(a), (b), and
(c) by failing to articulate the deficiencies in Discovery's
application during the review process.
Section 314.102 refers to reasonable efforts at notification of
easily correctable efficiencies or the need for additional data.
Section 314.103 establishes a process for dispute resolution.
The record reflects that Discovery's NDA was not under review until
December 7, 1992, at which time Discovery was fully apprised of the
application's deficiencies. See letter dated January 17, 1992, from Dr.
Paul Leber, FDA, to Mr. James T. Kimball, president of Discovery, with
attachment; transcript of the informal meeting between FDA and
Discovery held on November 16, 1992; letter dated December 7, 1992,
from Mr. James T. Kimball to Dr. Paul Leber, FDA; and letter dated
December 31, 1992, from Dr. Paul Leber to Mr. James T. Kimball.
Discovery submitted NDA 20-242 on November 29, 1991, and amended
its application on December 6, 1991. In a letter dated January 17,
1992, FDA informed Discovery that its submission was facially
deficient, listed the deficiencies in an attachment, and notified
Discovery that FDA refused to file the NDA. At this time, the NDA was
not under review by FDA. Discovery was again informed of the
deficiencies during an informal conference held with FDA on November
16, 1992. On December 7, 1992, Discovery requested that FDA file NDA
20-242 over protest.
Thus, NDA 20-242 was not under review by FDA until December 7,
1992, when the agency filed it over protest. At that time, Discovery
had already been informed of the substantial deficiencies in its NDA as
a result of the January 17, 1992, letter, and the November 16, 1992,
conference. In a letter dated August 20, 1993, FDA informed Discovery
that its NDA was not approvable and listed in detail numerous
significant deficiencies. Based on this record, it is clear that FDA
articulated the deficiencies in NDA 20-242 to Discovery before the
review process even began and thus gave Discovery an opportunity to
correct the
[[Page 15907]]
deficiencies before it filed Discovery's NDA for review over protest.
Although FDA did not communicate with Discovery after it began its
review of NDA 20-242 over protest, it had already done so on two
occasions before its review process began, thus fulfilling the intent
of the regulations. FDA had communicated the type of information
contemplated by Secs. 314.102(a) and (b) and 314.103(a), (b), and (c)
to Discovery before the review began.
Consequently, I find that this allegation by Discovery does not
raise a genuine and substantial issue of fact. Therefore, this
allegation does not justify a hearing (Secs. 12.24(b)(1) and
314.200(g)).
h. FDA violated Sec. 314.100 (21 CFR 314.100) by not notifying
Discovery that its application was approved within 180 days of its
receipt or disapproved.
Section 314.100 states that within 180 days of receipt of an NDA,
FDA will review it and send the applicant either an approval letter or
a not approvable letter.
Discovery submitted NDA 20-242 on November 29, 1991, and amended it
on December 6, 1991. As stated above, however, Discovery's NDA was not
filed until December 7, 1992. FDA issued its not approvable letter on
August 20, 1993. Whether measured from November 29, 1991; December 6,
1991; or December 7, 1992, FDA did not meet the 180-day deadline. There
is no issue of fact with regard to this point (Pineapple Growers Assoc.
of Hawaii, 673 F.2d at 1086).
The consequence of FDA delay in approving or disapproving an NDA,
however, is not the approval of the NDA. Federal courts have recognized
that the proper remedy of a party seeking to enforce a statutory
deadline is to seek an order compelling the agency to act, not to
challenge the legitimacy of post-deadline agency action. The Federal
courts have also recognized that if an agency's regulations do not
specify the consequence for noncompliance with regulatory timing
provisions, as is the case here, then the provision is merely directory
rather than mandatory. In such cases, Federal courts will not
ordinarily impose their own sanction nor will they seek to reorder
agency priorities.\9\
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\9\ See In re. Barr Laboratories, Inc., 930 F.2d 72, 76 (D.C.
Cir. 1991); Brotherhood of Railway Carmen v. Pena, 64 F.3d 702, 704
(D.C. Cir. 1995); United States v. James Daniel Good Real Property,
510 U.S. 43, 62-65 (1993).
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Discovery has made no showing that FDA did not respond to
Discovery's NDA as quickly as possible given the competing demands on
its resources. In light of the failure of Discovery to demonstrate that
its product is safe and effective, I find that there is no basis,
consistent with the act, to grant it the relief it seeks.
i.-m. FDA committed five ``illegalities'' with respect to its
approval of an NDA submitted by Somerset Pharmaceuticals, Inc. for its
Eldepryl product.
The five illegalities asserted by Discovery are based upon
Discovery's allegation that, at the time of its approval by FDA,
Eldepryl was contaminated with methamphetamine and
amphetamine, both of which are controlled substances under laws
administered by the Drug Enforcement Agency. Discovery did not submit
any evidence to support its allegation. On p. 32 of its response,
Discovery merely stated that it ``is fully prepared to argue and prove
that Eldepryl, prior to 1993, was contaminated with a high
degree of methamphetamine and amphetamine, and was not selegiline
hydrochloride but a contaminated version of selegiline hydrochloride.''
Discovery further alleged that FDA violated various sections of FDA
regulations and law by: Approving Eldepryl knowing it to
contain controlled substances; failing to require that
Eldepryl labels declare the presence of the controlled
substances; allowing the importation and distribution of
Eldepryl; failing to require that Somerset notify DEA of the
presence of controlled substances in its Eldepryl product;
and causing all pharmacists filling prescriptions of Eldepryl
to violate the law.
Discovery submitted no evidence in support of its allegation that
Eldepryl was contaminated with controlled substances when it
was approved and that FDA was aware of this fact. Discovery's mere
allegations, therefore, do not raise a genuine and substantial issue of
fact requiring a hearing (Secs. 12.24(b)(2) and 314.200(g)).
Moreover, Discovery's response to the NOOH failed to make clear the
relevance of FDA's approval and regulation of Somerset's
Eldepryl to the issue of whether Discovery's NDA 20-242 for
Deprenyl was approvable. In the absence of some reason to conclude
otherwise, I find that FDA's approval and regulation of
Eldepryl are irrelevant to the issue before me, i.e., the
approvability of NDA 20-242. FDA approval of another drug product does
not exempt Discovery's NDA from compliance with the new drug provisions
of the act. Resolution of Discovery's allegations, therefore, is not
probative of the approvability of NDA 20-242.
B. Statutory and Regulatory Framework
The act provides that:
Any person may file with the Secretary an application with
respect to any drug subject to the provisions of subsection (a) of
this section. Such person shall submit to the Secretary as a part of
the application (A) full reports of investigations which have been
made to show whether or not such drug is safe for use and whether
such drug is effective in use; (B) a full list of the articles used
as components of such drug; (C) a full statement of the composition
of such drug; (D) a full description of the methods used in, and the
facilities and controls used for, the manufacture, processing, and
packing of such drug; (E) such samples of such drug and of the
articles used as components thereof as the Secretary may require;
and (F) specimens of the labeling proposed to be used for such
drug.\10\
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\10\ Section 314.50 (21 CFR 314.50) sets out what is required to
be in such ``full'' reports, statements, and descriptions. The
regulation requires an NDA to contain, among other information, a
full description of the composition, manufacture, and specifications
of the drug substance and the drug product; an environmental
assessment or a claim for exclusion; the results of nonclinical
studies necessary to assess the pharmacological and toxicological
profile of the drug or clinical data to obviate the need for such
studies; the results of clinical studies necessary to assess the
safety and efficacy of the drug product; the proposed labeling of
the drug product; evidence demonstrating the in vivo bioavailability
of the drug product or information which would permit FDA to waive
such data; and compliance with FDA's current good manufacturing
practice (CGMP) regulations for finished pharmaceuticals (parts 210
and 211 (21 CFR parts 210 and 211)).
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Section 505(b)(1) of the act
The act requires that:
If the Secretary, [and by delegation of authority, the
Commissioner of Food and Drugs] finds, after due notice to the
applicant in accordance with subsection (c) of this section and
giving him an opportunity for a hearing, in accordance with said
subsection, that:
* * * * *
(3) the methods used in, and the facilities and controls used
for, the manufacture, processing, and packing of such drug are
inadequate to preserve its identity, strength, quality, and purity;
(4) upon the basis of the information submitted to him as part
of the application, or upon the basis of any other information
before him with respect to such drug, he has insufficient
information to determine whether such drug is safe for use under
such conditions; or
(5) evaluated on the basis of the information submitted to him
as part of the application and any other information before him with
respect to such drug, there is a lack of substantial evidence that
the drug will have the effect it purports or is represented to have
under the condition of use prescribed, recommended, or suggested in
the proposed labeling thereof; * * * he shall issue an order
refusing to approve the application.
[[Page 15908]]
Section 505(d) of the act\11\
---------------------------------------------------------------------------
\11\ Section 314.125(b) (21 CFR 314.125(b)) sets forth
additional reasons for which FDA may refuse to approve an NDA,
including: The absence of bioavailability data required by part 320
(21 CFR part 320); the failure of drug products' proposed labeling
to comply with the requirements for labels and labeling in part 201
(21 CFR part 201); and the failure to assure that the methods to be
used in, and the facilities and controls used for, the manufacture,
processing, packing, or holding of the drug substance or the drug
product comply with the CGMP regulations in parts 210 and 211.
Further, Sec. 314.125(a)(3) states that FDA may refuse to approve an
NDA for any of the reasons listed in Sec. 314.125(b).
---------------------------------------------------------------------------
C. Evidence of Safety
For approval of its NDA, Discovery was required to submit to FDA,
among other information, ``full reports of investigations which have
been made to show, whether or not such drug is safe for use * * *,'' as
required by section 505(b)(1) of the act, as well as all information
required by Sec. 314.50.
In the NOOH, FDA stated that NDA 20-242 failed to contain any
nonclinical studies\12\ necessary to assess the safety of the drug or
any clinical data to obviate the need for such studies; that the copies
of published studies Discovery submitted in support of the safety of
Deprenyl were not performed using its product; and that it was apparent
from the NDA that Discovery had sought to use the safety studies
contained in an NDA for another FDA approved product,
Eldepryl, manufactured by Somerset, as evidence of the safety
of its Deprenyl product, which it could not do.\13\
---------------------------------------------------------------------------
\12\ Nonclinical studies are studies involving animals as test
subjects and are designed to determine if the new drug is safe for
use in humans.
\13\ FDA notified Discovery in its ``not approvable letter''
dated August 20, 1993, that Somerset was granted exclusive marketing
for Eldepryl in NDA 19-338 for 5 years from the date of
its approval (June 5, 1989) and that section 505(c)(3)(D)(ii) of the
act prohibited anyone from submitting an NDA seeking to use the
safety and efficacy data contained in the approved application for
any other form of the drug (including other salts, esters, etc.)
until the exclusivity period expired (June 6, 1994).
---------------------------------------------------------------------------
In its response, Discovery made three arguments related to the
safety of Deprenyl: that Deprenyl was as safe as Eldepryl,
therefore, FDA should have approved Deprenyl; that Discovery had
submitted 29 studies in its NDA that established the safety of
Deprenyl; and that FDA had collected a sample of Deprenyl and purposely
withheld the results of its analysis from publication in the NOOH. I
will consider each of these arguments to see, first, whether they
justify granting a hearing, and second, whether they would justify a
finding that Deprenyl is safe.
1. Deprenyl is as Safe as Eldepryl
Eldepryl is currently being marketed by Somerset for the
treatment of Parkinson's disease. However, when Discovery's NDA was
filed, Somerset still enjoyed its exclusivity period granted by the act
(section 505(c)(3)(D)(ii) of the act and 21 CFR 314.108). Thus,
Discovery was prohibited by the act from using any of the data
contained in the Eldepryl NDA to support its NDA for
Deprenyl.\14\
---------------------------------------------------------------------------
\14\ Somerset's exclusivity period expired on June 6, 1994. This
fact is not relevant to this proceeding because I am reviewing an
application that was filed before that date. I express no view as to
the significance of the safety and effectiveness data in NDA 19-338
(Eldepryl) for Discovery's application because that
question is not before me.
---------------------------------------------------------------------------
Barred by the act from using any information contained in the
Eldepryl NDA, Discovery's mere reassertion in its response to
the NOOH that its product is as safe as Eldepryl does not
raise a genuine and substantial issue of fact requiring a hearing.
Discovery has not presented any data or other evidence to support its
assertion (Secs. 12.24(b)(2) and 314.200(g)).
Discovery did not challenge FDA's statement in the NOOH that
Discovery claimed that its product is not the same as the FDA-approved
product, Eldepryl. Indeed, Discovery stated that:
[It] is fully prepared to argue and prove that Eldepryl, prior
to 1993, was contaminated with a high degree of methamphetamine and
amphetamine, and was not selegiline hydrochloride but a contaminated
version of selegiline hydrochloride. These contaminants in Eldepryl
lessen the effectiveness of the selegiline. Thus, the product is not
selegiline or selegiline hydrochloride as approved by the FDA, but
selegiline hydrochloride plus methamphetamine and amphetamine * * *.
Even with the improvements made in the methamphetamine/amphetamine
content of Eldepryl in 1993, and as reformulated, the Eldepryl
product still contains methamphetamine, unlike [Discovery's]
selegiline in which the methamphetamine content is, in essence,
unmeasurable. * * * [n]o one has made deprenyl that compares to the
purity of [Discovery's] product * * * . Products made without
contaminates, in their purest form, prove much safer and effective
than the contaminated products allowed by the FDA.
Discovery response to NOOH, pp. 32-34
Finally, Discovery failed to challenge the absence in its NDA of a
``right of reference'' to the Eldepryl NDA or FDA's finding
that it (Discovery) had failed to otherwise comply with the
requirements of section 505(b)(2) of the act.\15\
---------------------------------------------------------------------------
\15\ Absent a right of reference, Discovery would have had to
comply with other requirements of section 505(b)(2) of the act,
including that Discovery submit a certification that the patent for
Eldepryl did not apply, which it did not do.
---------------------------------------------------------------------------
Notwithstanding the statutory prohibition against Discovery using
safety data contained in the Eldepryl NDA, Discovery's
admission that its product is different than Eldepryl alone
is fatal to its argument that the safety of Deprenyl could be
established by comparing it to the approved product,
Eldepryl. Therefore, I find no merit to the first of
Discovery's three assertions on the safety of Deprenyl.
2. Discovery Submitted 29 Trials that Showed Deprenyl to be Safe
In its response to the NOOH, Discovery asserted that its product
``has been proven safe in over 30 years of clinical use,'' and that
Deprenyl ``has unequivocally proven to be one of the safest, if not the
safest product to take'' for the treatment of Alzheimer's disease
(Discovery response, pp. 31, 40). Discovery did not present any safety
studies in its response. Instead, it stated that:
it saw absolutely no rationale for conducting clinical safety
tests with deprenyl, when [Discovery] submitted at least 29 trials
[in its NDA] that stated, in essence, that deprenyl is safer than
most pharmaceuticals on the market [and] safer than raw seafood or
uncooked fresh fruits and vegetables * * *.
Discovery response, p. 31
Discovery did not identify which of the 171 published studies it
submitted in its NDA were the 29 that it believed established the
safety of Deprenyl.
As stated in the NOOH, Discovery could have established the safety
of Deprenyl in its NDA in two ways. Either it could have performed and
submitted the necessary toxicological and pharmacological studies on
its product, or it could have submitted clinical data to obviate the
need for such data. In its response, Discovery does not contest the
absence of pharmacological or toxicological studies in its NDA.
Discovery does, however, assert that it submitted 29 studies in its NDA
that established the safety of Deprenyl.
In the NOOH, FDA explained that it could not accept any of the 171
published studies submitted in NDA 20-242 as evidence of the safety of
Discovery's product because none of the studies used Discovery's
product. Any study purporting to compare the safety of Discovery's
product to other pharmaceutical products on the market, or to raw
seafood and uncooked fresh fruits and vegetables, would have to use
Discovery's product as a test article or one shown to be bioequivalent
to Discovery's product. Because none of the published studies submitted
in NDA 20-242 used Discovery's product, and Discovery did not submit
any information showing that any of the test articles used in the
studies was bioequivalent to its product, none of the
[[Page 15909]]
studies could be used to make such comparisons nor to reach such
conclusions.
In its response, Discovery did not challenge FDA's statements in
the NOOH that NDA 20-242 failed to contain any safety studies of
Deprenyl, preclinical or clinical, and that the 171 studies it
submitted were not conducted using its product. Discovery thus fails to
raise an issue of fact requiring a hearing (Secs. 12.24(b)(1) and
314.200(g)). Discovery's mere assertions that its product has been
proven safe; that it is has been proven to be one of the safest
products to take for the treatment of Alzheimer's disease; that it is
safer than most pharmaceuticals on the market; and that it is safer
than raw seafood or uncooked fresh fruits and vegetables are not
sufficient to raise a genuine and substantial issue of fact requiring a
hearing, Secs. 12.24(b)(2) and 314.200(g), or to establish the safety
of its product. Therefore, I find that Discovery's second allegation is
also without merit.
3. FDA's Analytical Evidence Showed Deprenyl to be Safe
Finally, Discovery asserted that FDA had collected a sample of 50
bottles of its product during an FDA inspection of Discovery and had
``conveniently'' left the results out of the NOOH, implying that the
results were favorable to Discovery. Discovery submitted no evidence
that FDA had performed any safety studies using the sample it collected
from Discovery (Discovery response, p. 33).
FDA has no obligation to, nor does it, use the results of tests
performed on samples that it collects during an inspection as a
substitute for safety studies conducted by a sponsor in support of
approval of a new drug product. The act places the burden of
establishing the safety of a new drug on the NDA sponsor, not FDA
(section 505(b)(1) of the act).
Moreover, with respect to the sample of Discovery's product
collected by FDA investigators, in its response to the NOOH Discovery
admitted that it ``held back DELIBERATELY, due to MISTRUST, the PUREST
LIQUID DEPRENYL product [from the FDA investigators] which would have
been put into [its] production runs'' (Discovery response, p. 8
(emphasis in original)). Thus, notwithstanding the fact that the act
places the burden for safety studies on the applicant, even if FDA did
perform safety studies using the sample collected during the
inspection, such studies could not demonstrate the safety of the form
of the product that Discovery itself says that it uses. Thus,
Discovery's third assertion neither suggests the existence of an issue
of fact that would justify a hearing nor the existence of evidence to
establish the safety of Discovery's product.
In sum, Discovery offered no evidence in its response to challenge
FDA's conclusion in the NOOH that NDA 20-242 was not approvable because
it failed to contain any safety studies of Deprenyl, preclinical or
clinical, or that the studies it submitted as part of its NDA were not
acceptable as evidence of Deprenyl's safety because the studies were
not conducted with its product. Mere assertions that Discovery's
product is safe are insufficient to raise a genuine and substantial
issue of fact requiring a hearing. Discovery's failure to present any
evidence establishing the safety of its product requires, in and of
itself, summary judgment against Discovery and disapproval of NDA 20-
242 (Secs. 12.24(b)(1) and (b)(2), 314.200(g), and section 505(d)(4) of
the act).
D. Evidence of Effectiveness
In addition to evidence of safety, to obtain approval of NDA 20-
242, Discovery was required to submit, among other information, full
reports of investigations that were made to show whether or not
Deprenyl is effective in use (section 505(b)(1) of the act and
Sec. 314.50).
In its NDA, Discovery proposed to label Deprenyl as effective for
the treatment of Alzheimer's disease and claimed that its product
demonstrated a ``quantitative and qualitative improvement in cognitive
functions of Alzheimer's patients as a result of the inhibition of MAO-
B activity.'' To support the statutory requirement for adequate and
well-controlled studies that demonstrate the effectiveness of Deprenyl,
Discovery submitted in its NDA reprints from 171 articles published in
the medical and scientific literature, specifically identifying in the
table of contents 12 of these 171 articles as evidence of the
effectiveness of deprenyl citrate in the treatment of Alzheimer's
disease.
In the NOOH, FDA explained in general why it could not accept any
of the 171 published studies submitted in NDA 20-242 as evidence of the
effectiveness of Deprenyl. The agency pointed out that even though some
of these articles pertained to deprenyl, not one of the studies used
Discovery's product or a product with a known bioavailability
relationship to Discovery's product.
Regarding the 12 published studies identified in the NDA's table of
contents as evidence supporting the effectiveness of Deprenyl, the NOOH
explained the reasons why each one was inherently incapable of being
regarded as substantial evidence of the effectiveness of deprenyl
citrate in the treatment of Alzheimer's disease, as follows:
Study No. 1: Mangoni, A. et al., ``Effects of a MAO-B Inhibitor in
the Treatment of Alzheimer Disease,'' European Neurology, 31:100-107,
1991.
While finding that this study suggested a positive effect of L-
deprenyl in patients with Alzheimer's disease, the agency found that
the published report lacked many details required by FDA's regulations
to enable the agency to assess the study, including data from a
bioequivalence study that demonstrates that the rate and the extent of
absorption of Deprenyl are essentially identical to the product used in
the published study (Secs. 320.21 and 314.126(d)); a protocol to
determine whether the study design and analysis, including analysis of
patients not completing the study, were performed as proposed
(Secs. 314.50 and 314.126(b)(1)); the measures used to minimize bias in
the study such as the details of randomization, blinding, maintenance
of patient assignment code, including an explanation for the unequal
number of patients treated with the drug versus the number receiving a
placebo (Sec. 314.126(b)(5); and copies of case report forms or data
tabulations, and individual patient data on safety and effectiveness
measures (Secs. 314.50 and 314.126(a)).
Study No. 2: Knoll, J., J. Dallo, and T. T. Yen: ``Striatal
Dopamine, Sexual Activity and Lifespan. Longevity of Rats Treated With
(-) Deprenyl,'' Life Sciences, 45:525-531, 1989. This study was not an
adequate and a well-controlled clinical study of the effectiveness of
deprenyl citrate in the treatment of Alzheimer's disease because it was
a study in rats and not a clinical (human) study.
Study No. 3: Heinonen, E. H. et al., ``Pharmacokinetics and
Metabolism of Selegiline,'' Acta Neurologica Scandinavia, 126:93-99,
1989. This study was not an adequate and a well-controlled clinical
study of the effectiveness of deprenyl citrate in the treatment of
Alzheimer's disease because the clear objective of the study was to
study the pharmacokinetics, not the effectiveness, of selegiline
(deprenyl).
Study No. 4: Shoulson, I. et al. (The Parkinson Study Group),
``Effect of Deprenyl on the Progression of Disability in Early
Parkinson's Disease,'' The New England Journal of Medicine, 321:1364-
1370, 1992. This study was not an adequate and a well-controlled
clinical study of the effectiveness of
[[Page 15910]]
deprenyl citrate in the treatment of Alzheimer's disease because it was
a study of Parkinson's, and not Alzheimer's, disease.
Study No. 5: Tariot, P. N. et al., ``Cognitive Effects of L-
Deprenyl in Alzheimer's Disease,'' Psychopharmacology, 91:489-495,
1987. This study was not an adequate and a well-controlled clinical
study of the effectiveness of deprenyl citrate in the treatment of
Alzheimer's disease because there was no protocol available to provide
details of the study; the study did not use a randomized concurrent
control or other means of assuring comparability of treatment and
control groups; the procedures used to minimize bias, such as blinding,
were not described; and the test drug was not identified.
Study No. 6: Tariot, P. N. et al., ``L-Deprenyl in Alzheimer's
Disease: Preliminary Evidence for Behavioral Change With Monoamine
Oxidase B Inhibition,'' Archives of General Psychiatry, 44:427-433,
1987. This was a preliminary report of the data from the Tariot study
described under Study No. 5 above. Therefore, it suffers from the same
deficiencies cited above.
Study No. 7: Tariot, P. N. et al., ``Tranylcypromine Compared With
L-Deprenyl in Alzheimer's Disease,'' Journal of Clinical
Psychopharmacology, 8:23-27, 1988. This study was not an adequate and a
well-controlled clinical study of the effectiveness of deprenyl citrate
in the treatment of Alzheimer's disease because its primary purpose was
to investigate tranylcypromine, a drug of unknown effectiveness in the
treatment of Alzheimer's disease.
Study No. 8: Sunderland, T. et al., ``Dose-Dependent Effects of
Deprenyl on CSF Monoamine Metabolites in Patients With Alzheimer's
Disease,'' Psychopharmacology, 91:293-296, 1987. This study was not an
adequate and a well-controlled clinical study of the effectiveness of
deprenyl citrate in the treatment of Alzheimer's disease because the
clear objective of the study was to study the pharmacokinetics, not the
effectiveness, of deprenyl.
Study No. 9: Konradi, C., P. Riederer, and M. B. H. Youdim,
``Hydrogen Peroxide Enhances the Activity of Monoamine Oxidase Type-B
But Not of Type-A: A Pilot Study,'' Journal of Neural Transmission,
Suppl. 22:61-73, 1986. This study was not an adequate and a well-
controlled clinical study of the effectiveness of deprenyl citrate in
the treatment of Alzheimer's disease because its primary purpose was
the study of the effects in certain tissues of hydrogen peroxide, not
deprenyl citrate, and it was not a clinical study, i.e., a study in
human patients with the disease intended to be treated.
Study No. 10: Maurizi, C. P., ``The Therapeutic Potential for
Tryptophan and Melatonin: Possible Roles in Depression, Sleep,
Alzheimer's Disease and Abnormal Aging,'' Medical Hypotheses, 31:233-
242, 1990. This review article was not an adequate and a well-
controlled clinical study of the effectiveness of deprenyl citrate in
the treatment of Alzheimer's disease because it was not the report of
an investigation, and moreover, it did not even mention the drugs
deprenyl or selegiline.
Study No. 11: Knoll, J., ``The (-)Deprenyl-Medication: A Strategy
To Modulate the Age-Related Decline of the Striatal Dopaminergic
System,'' Journal of the American Geriatric Society, 40:839-847, 1992.
This review article was not an adequate and a well-controlled clinical
study of the effectiveness of deprenyl citrate in the treatment of
Alzheimer's disease because it was not the report of an investigation.
Study No. 12: Martini, E. et al., ``Brief Information an Early
Phase-II Study With Deprenyl in Demented Patients,''
Pharmacopsychiatry, 20:256-257, 1987. This 11-patient uncontrolled
study was not an adequate and a well-controlled clinical study of the
effectiveness of deprenyl citrate in the treatment of Alzheimer's
disease because it was not the report of an investigation that
permitted a valid comparison with a control.
In its response to the NOOH, Discovery did not challenge FDA's
statement that none of the 171 articles contained in NDA 20-242
involved studies that used its product or a product with a known
bioavailability relationship to its product. Nor did it challenge the
reasons cited in the NOOH as to why the 12 published studies that it
highlighted in its NDA were not adequate to support evidence of the
effectiveness of Discovery's product.
Instead, Discovery submitted abstracts of studies Nos. 1 and 5;
quoted from study articles Nos. 1 and 5; and merely asserted that: (1)
``the trial publications submitted by [Discovery], not only should
indicate to any normal human being that deprenyl is effective in
Alzheimer's Disease * * *.''; (2) ``[a]ll journal trials submitted
referenced definite improvement in people afflicted with Alzheimer's
Disease treated with deprenyl since 1985''; and (3) ``Not only has the
product unequivocally proven to be effective in the treatment of
Alzheimer's, but has unequivocally proven to be one of the safest, if
not the safest product to take'' (Discovery response, pp. 36 and 39-
40).
Discovery's responses fail to raise a genuine and substantial issue
of fact requiring a hearing. First, the abstracts of studies Nos. 1 and
5 provided by Discovery in its response included no new information
that had not already been submitted in the NDA. Second, Discovery did
not explain how or why the quoted statements from the studies already
submitted and reviewed by FDA should be found adequate to fulfill the
statutory requirements for adequate and well-controlled studies of the
effectiveness of its product. Third, Discovery's response consisted of
mere allegations that its product was effective. A hearing, therefore,
is not required (Secs. 12.24(b)(1) and (b)(2) and 314.200(g)).
Discovery also alleged in its response that: (1) FDA did not review
all 2,000 pages of the 171 published articles submitted in the NDA, and
(2) that FDA reviewed NDA 20-242 based upon an incorrect table of
contents instead of an amended table of contents submitted after its
NDA was filed over protest.
Regarding the first allegation, FDA advised Discovery in its ``not
approvable letter'' dated August 20, 1993, that it had reviewed the
published literature provided in its application. (See letter dated
August 20, 1993, from Robert Temple to James T. Kimball, p. 3.)
Discovery did not submit any evidence to challenge this statement.
Therefore, it did not justify a hearing (Secs. 12.24(b)(2) and
314.200(g)).
Regarding the second allegation, notwithstanding the fact that FDA
was only obligated to review NDA 20-242 as filed over protest, even if
FDA were to have reviewed the amended table of contents, it would not
have altered FDA's review of the material that was filed. As stated in
its letter to Discovery, FDA had reviewed the studies that Discovery
submitted in its NDA, and Discovery did not identify any specific
evidence or specific studies that FDA failed to review that addressed
the deficiencies in NDA 20-242 raised in the NOOH. Discovery's
response, therefore, consisted of mere allegations, which do not raise
a genuine and substantial issue of fact requiring a hearing
(Secs. 12.24(b)(2) and 314.200(g)).
Moreover, Discovery's failure to challenge substantively FDA's
assertion that none of the 171 studies related to the effectiveness of
its product or to a product with a known bioavailability relationship
to its product deprives Discovery's allegation of significance as far
as justifying a hearing is concerned. If FDA had failed to review any
of the
[[Page 15911]]
171 studies submitted, such a failure would be significant if Discovery
had alleged that FDA's failure had caused it to miss evidence that
would justify granting the NDA. Discovery makes no such claim. Thus,
Discovery has not presented an issue that warrants a hearing
(Secs. 12.24(b)(4) and 314.200(g)).
Finally, Discovery alleged that FDA approved a different, more
dangerous, and less effective product than Discovery's product for the
treatment of Alzheimer's disease when it approved Tacrine Hydrochloride
(Cognex , Parke-Davis) (Discovery response, p. 41). FDA's
approval of another drug product is irrelevant to the question of
whether NDA 20-242 meets the requirements in section 505(b) of the act
and Sec. 314.50. FDA approval of another drug product does not exempt
Discovery's NDA from compliance with the new drug provisions of the
act. Discovery's allegations, therefore, do not raise a genuine and
substantial issue of fact regarding FDA's proposal to refuse to approve
NDA 20-242 because it failed to contain information required by section
505(b) of the act and Sec. 314.50. A hearing, therefore, is not
required (Secs. 12.24(b)(1) and 314.200(g)).
In sum, Discovery failed to raise a genuine and substantial issue
of fact regarding FDA's findings in the NOOH that Discovery had failed
to comply with the requirements of section 505(b)(1)(A) of the act and
Sec. 314.50. Thus, FDA's findings stand unchallenged. Discovery's
failure to present any evidence establishing the effectiveness of its
product requires, in and of itself, summary judgment against Discovery
and disapproval of NDA 20-242 (section 505(d)(5) of the act).
E. Methods, Facilities, and Controls
To gain approval of its NDA, Discovery was required to submit
information in NDA 20-242 that the methods to be used in, and the
facilities and controls used for, the manufacture, processing, packing,
and holding of the drug substance and the drug product were adequate to
preserve the identity, strength, quality, purity, stability, and
bioavailability of the drug substance and the drug product
(Sec. 314.50(d)(1)(i) and (d)(1)(ii)(a)).
In the NOOH, FDA stated that the deficiencies in Discovery's NDA
related to the drug substance included a lack of information concerning
the methods used in the synthesis, extraction, isolation, and
purification of the new drug substance to determine its identity,
strength, quality, and purity. With respect to the drug product, the
NOOH stated that Discovery's NDA lacked information about the drug
product components, composition, and formulation; how the drug product
was to be manufactured; the laboratory methods to be used to test the
drug product, including validation of the test methods; and the product
container system and packaging to be used for the drug product.
Discovery's reply to this issue appears on pp. 42-43 and 50-53 of
its response and consists of the following:
1. With respect to the absence of information in NDA 20-242 about
the methods, facilities, and controls used for the manufacture of
Deprenyl, Discovery stated in its response that, ``The absolute facts
are that the FDA inspectors, who spent four days at [Discovery's]
facility, found none of the above,'' and that ``[t]he FDA inspection of
February, 1993 confirmed the methods and procedures used by [Discovery]
in the formulation and bottling of the product exceeded FDA standards''
(Discovery response, pp. 42 and 51).
Discovery's response did not address the deficiency in NDA 20-242
that was cited in the NOOH. In the NOOH, FDA stated that NDA 20-242
failed to contain certain information concerning: The drug substance;
the drug product; methods validation; stability data; establishment
locations; and an environmental assessment. In its response, Discovery
did not challenge that this information was not included in its NDA.
Discovery, therefore, failed to raise a genuine and substantial issue
of fact requiring a hearing (Secs. 12.24(b)(1) and 314.200(g)). Without
this information, it obviously was not possible for FDA to do the type
of evaluation that was necessary to assess the safety and effectiveness
of a new drug.
2. ``[T]he method used in the manufacture of deprenyl by
[Discovery] is a trade secret. It was kept so due to the total mistrust
of the FDA * * * '' (Discovery response, p. 50).
Discovery's response is an admission that it did not provide FDA
with information about the manufacture of Deprenyl. Such information is
required to be in an NDA by the act (section 505(b)(1)(D) of the act).
Because Discovery's response does not challenge the absence of such
information in NDA 20-242, Discovery's response does not raise a
genuine and substantial issue of fact requiring a hearing
(Secs. 12.24(b)(1) and 314.200(g)). Moreover, Discovery conceded that
its application did not comply with the act.
3. ``The evidence submitted to the FDA unequivocally proved that
[Discovery's] deprenyl is deprenyl'' (Discovery response, p. 51).
Discovery's response did not challenge FDA's statements in the NOOH
that NDA 20-242 lacked the information about the drug substance and the
drug product required by Sec. 314.50(d)(1)(i) and (d)(1)(ii)(a).
Discovery's response, therefore, does not raise a genuine and
substantial issue of fact requiring a hearing (Secs. 12.24(b)(1) and
314.200(g)).
4. ``How a product is manufactured should be of no concern to the
FDA, only the purity of the end product[,]'' and ``[t]he methods of
manufacture, in essence, mean absolutely nothing, as long as the end
product is a pure and chemically correct product'' (Discovery response,
pp. 50-51).
FDA is required by statute to review the manufacturing process of a
new drug in its review of an NDA (section 505(d)(3) of the act). In
addition, Congress has recognized the connection between the purity of
a drug and the manner in which it is manufactured by the fact that any
drug not manufactured in conformity with current good manufacturing
practices is deemed adulterated (section 501(a)(2)(B) of the act (21
U.S.C. 351(a)(2)(B))). Discovery's response, therefore, does not raise
an issue of fact, Secs. 12.24(b)(1) and 314.200(g), but concedes that
it has not complied with the act. If Discovery wishes to change the law
as to whether how a product is manufactured is of significance, its
venue is the Congress. I must enforce the act as written, and given
that state of affairs, the record establishes that Discovery's
application is deficient.
5. ``[Discovery] is fully prepared to prove that if a product, is a
product chemically, then it unequivocally is that product'' (Discovery
response, p. 43).
Discovery's response does not challenge FDA's statement in the NOOH
that Discovery's NDA lacked the information required by the act. The
fact that Discovery is fully prepared to prove its statement is
insufficient to raise a genuine and substantial issue of fact. The
opportunity to offer evidence in support of its assertion was in
response to the NOOH. Discovery's response, therefore, does not raise a
genuine and substantial issue of fact requiring a hearing
(Secs. 12.24(b)(1) and 314.200(g)).
6. Regarding the absence of an environmental statement in its NDA
Discovery stated that:
[T]he EPA stated that the manufacturing methods of Liquid
Deprenyl Citrate being used by [Discovery] did not warrant an
inspection, and that the EPA would not inspect [Discovery] as
[Discovery] was in total compliance. The FDA's duplication of the
EPA's jurisdiction is ludicrous and totally redundant.
[[Page 15912]]
Discovery response, p. 52
FDA regulations require an NDA to contain an environmental
assessment under 21 CFR 25.31, or a claim for exclusion under 21 CFR
25.24 (Sec. 314.50(d)(1)(iii) and 21 CFR 25.22(a)(14)).
In the NOOH, FDA stated that Discovery had not claimed exclusion,
and that NDA 20-242 was facially unresponsive to FDA's regulatory
requirement in that it was lacking identification of the chemical
substances that were the subject of the assessment. Discovery's
response, therefore, that FDA's requirements are duplicative of the
Environmental Protection Agency's (EPA's) requirements, raises an issue
of law rather than an issue of fact, which does not require a hearing
(Secs. 12.24(b)(1) and 314.200(g)).
Furthermore, Discovery's response amounts to a request that FDA
ignore the requirements of its existing regulations. Discovery's
response, therefore, is inconsistent with the provisions of FDA's
regulatory requirements and, therefore, is wrong as a matter of law.
FDA's environmental assessment regulations were issued to implement
the requirements of EPA, under which each agency must assess the
effects of its actions (40 CFR 1506.5(b) and 21 CFR part 25). Nothing
in what Discovery reports EPA as saying is in derogation of that fact.
Therefore, there is no merit to Discovery's claim, and I find that
Discovery's application is deficient in this regard. Thus, Discovery
failed to raise an issue of fact that would justify a hearing
(Secs. 12.24(b)(5) and 314.200(g)).
7. FDA failed to post the results of its analysis of a sample of 50
bottles of Discovery's product collected during its February 1993,
inspection of Discovery (Discovery response, p. 42).
With respect to the sample of Discovery's product collected by FDA
investigators, Discovery cannot seriously suggest that FDA would use
this sample to establish, itself, the safety and effectiveness of
Discovery's product. First, as stated above, in its response to the
NOOH, Discovery admitted that it ``held back DELIBERATELY, due to
MISTRUST, the PUREST LIQUID DEPRENYL product [from the FDA
investigators] which would have been put into [its] production runs''
(Discovery response, p. 8 (emphasis in original)). Consequently, even
if FDA were to test the sample provided by Discovery for safety or
effectiveness, Discovery's admission that it did not provide FDA with
the most potent formulation of its drug product would render worthless
any such test results and render the issue not determinative of the
approvability of NDA 20-242. Thus, Discovery failed to raise an issue
of fact that would justify a hearing (Secs. 12.24(b)(1) and
314.200(g)).
Second, as a matter of law, the statute places these burdens on the
applicant. Thus, I find this allegation to be utterly without merit or
probative value (section 505(b) of the act).
In sum, Discovery's response either does not challenge FDA's
conclusion that NDA 20-242 lacked the information required by section
505(b)(1) of the act and Sec. 314.50(d)(1) or requests an action
inconsistent with the requirements of the act. Discovery thus fails to
raise a genuine and substantial issue of fact requiring a hearing
(Secs. 12.24(b)(1) and (b)(5) and 314.200(g)).
Discovery's failure to include information regarding the methods,
facilities, and controls to be used for the manufacture and control of
Deprenyl in NDA 20-242 requires, in and of itself, summary judgment
against Discovery and refusal to approve NDA 20-242 (section 505(d)(3)
of the act).
F. Drug Product Labeling
In the NOOH, FDA stated that, among other deficiencies related to
the proposed labeling of Deprenyl, NDA 20-242 did not contain copies of
the labeling to be used for the packaged drug product, as required by
Sec. 314.50(e)(2)(ii), and did not contain copies of the labeling to be
used for the shipment and storage of the bulk drug substance, as
required by Secs. 314.125(b)(8) and 201.122.
In its response, Discovery did not challenge the accuracy of FDA's
statements in the NOOH. Instead, Discovery contended that FDA had not
addressed any specific problem regarding the labeling of Deprenyl in
the NOOH, except to state that Discovery had proposed labeling of
Deprenyl for over-the-counter marketing, as opposed to distribution by
prescription.
Discovery's contention that FDA did not address in the NOOH any
specific labeling deficiencies associated with NDA 20-242 is belied by
the NOOH itself. In the NOOH (59 FR 26239 at 26243), FDA listed three
labeling deficiencies associated with NDA 20-242. I find, therefore,
that Discovery's contention is an error of fact. Thus, Discovery failed
to raise an issue of fact that would justify a hearing
(Secs. 12.24(b)(1) and 314.200(g)).
Discovery's contention that FDA raised the marketing status of
Deprenyl in the NOOH is also belied by the NOOH itself. The marketing
status of Deprenyl was not raised in the NOOH. The record does,
however, reflect that FDA raised the issue on p. 12 of its ``not
approvable'' letter to Discovery, dated August 20, 1993, under the
heading ``Proposed Marketing Status.'' I find, therefore, that
Discovery's contention is an error of fact. Thus, Discovery failed to
raise an issue of fact that would justify a hearing (Secs. 12.24(b)(1)
and 314.200(g)).
Discovery also alleged in its response that FDA rewrote the
labeling for Somerset when Somerset's labeling and packaging for
Eldepryl were found to be deficient--Discovery response, p.
53 and exhibit 10 (including a copy of a letter from FDA to Somerset to
which FDA attached a revised package insert for Eldepryl).
Because Discovery's response does not challenge FDA's finding in
the NOOH, it fails to raise a genuine and substantial issue of fact
requiring a hearing. Furthermore, evidence that FDA revised labeling
submitted in an NDA by another applicant does not address the absence
of such required labeling in NDA 20-242 and, therefore, is not
determinative with respect to the approvability of NDA 20-242. As such,
Discovery's allegation does not raise a genuine and substantial issue
of fact requiring a hearing (Secs. 12.24(b)(1) and (b)(4) and
314.200(g)).
Discovery's failure to include information required by
Sec. 201.122, in and of itself, is a sufficient basis upon which to
refuse to approve NDA 20-242 (Sec. 314.125(b)(8)).
G. Bioavailability Data
In order for Discovery to obtain approval of NDA 20-242, the
application had to contain either: (1) Evidence demonstrating the in
vivo bioavailability of the drug product, or (2) information that would
permit the agency to waive demonstration of in vivo bioavailability
(Secs. 314.50(d)(3) and 320.21(a)). In its NDA, Discovery contended
that it was entitled to a waiver of the demonstration of in vivo
bioavailability because the drug and its metabolites are not measurable
in plasma ``at their designated levels.''
In the NOOH, FDA stated that Discovery's conclusion was incorrect,
based upon two articles in the scientific literature that provided
information on the metabolites of selegiline (deprenyl). (See, Salonen,
J. S., ``Determination of the Amine Metabolites of Selegiline in
Biological Fluids by Capillary Gas Chromatography,'' Journal of
Chromatography, 527:163-168, 1990; Heinonen, E. H., and R.
Lammintausta, ``A Review of the Pharmacology of
[[Page 15913]]
Selegiline,'' Acta Neurologica Scandinavia, Suppl., 136:44-59, 1990.)
In response to the NOOH, Discovery merely asserted that,
In addition, the FDA reverts to bio-equivalency, and [Discovery]
will again unequivocally state that Liquid Deprenyl Citrate is
selegiline, period. Selegiline or selegiline hydrochloride was used
in all references. [Discovery] is prepared to prove that if a
product, is a product chemically, then it unequivocally is that
product.
Discovery response, p. 43
Discovery's response, which referred to ``bio-equivalency,'' did
not challenge FDA's assertion that NDA 20-242 lacked bioavailability
data, nor did it challenge the basis for FDA's conclusion that
bioavailability data could not be waived because published scientific
literature demonstrated that the metabolites of selegiline are
measurable.
As it did in response to other issues raised by FDA in the NOOH,
Discovery sought to fulfill its obligation to provide the information
required by the act and FDA by a mere assertion that its product is
what it purports to be. FDA regulations, however, require Discovery to
submit evidence of the bioavailability of its product or to obtain a
waiver of the requirement to submit such information. Mere assertions
of bioavailability are not sufficient to raise an issue of fact or to
fulfill the requirements for FDA approval of NDA 20-242.
Because Discovery failed to challenge FDA's conclusion in the NOOH
that its NDA failed to contain required bioavailability data, it failed
to raise an issue of fact requiring a hearing (Secs. 12.24(b)(1) and
314.200(g)). Discovery's mere assertion that its product is
bioequivalent to a drug substance is also insufficient to raise an
issue of fact requiring a hearing regarding the absence of
bioavailability data in NDA 20-242 (Secs. 12.24(b)(2) and 314.200(g)).
Discovery's failure to include bioavailability data in NDA 20-242
is a sufficient basis, in and of itself, to refuse to approve NDA 20-
242 (Sec. 314.125(b)(9)).
H. CGMP Requirements
In addition to the requirement that an NDA contain a description of
the manufacturing and packaging procedures and in-process controls
designed to assure the identity, strength, quality, purity, and
bioavailability of the drug substance and drug product
(Sec. 314.50(d)(1)(i) and (d)(1)(ii)(a)), FDA requires that an
applicant be in compliance with CGMP as set forth at parts 210 and 211
(Sec. 314.125(b)(13)).
Between February 25 and March 2, 1993, FDA investigators made an
inspection of Discovery's establishment in Wesley Chapel, FL, and the
investigators observed numerous violations of the CGMP regulations. The
following were among numerous CGMP violations observed during the
February through March, 1993, inspection.
1. Discovery lacked adequate standard operating procedures with
regard to: (a) Responsibilities of the quality control unit
(Sec. 211.22); (b) cleaning and maintenance of equipment used in
manufacturing products (Sec. 211.67); (c) receipt and handling of
components (Sec. 211.82); (d) production and process control, e.g.,
weighing components (Sec. 211.101); and (e) in-process controls or
testing (Sec. 211.110).
2. Discovery lacked a written stability program. Additionally,
Discovery could locate no records documenting stability testing of
selegiline citrate (Sec. 211.166).
3. Discovery could not produce batch production records showing
manufacture of the one batch produced, which was intended by the firm
for use in clinical trials (Sec. 211.188).
In its response to the NOOH, Discovery asserted that: (1) The
faults found in its NDA should have been addressed in the first 90 days
during the review of Discovery's application; (2) the CGMP violations
cited in the NOOH did not exist at the time of the FDA inspection; and
(3) the FDA investigators did not inform Discovery of the CGMP
violations at the time of their inspection (Discovery response, p. 52).
With respect to Discovery's first assertion, Discovery's response
did not address the issue raised by FDA in the NOOH. FDA's statements
regarding this issue in the NOOH did not pertain to the contents of
Discovery's NDA. Rather, they concerned the findings of an FDA
inspection conducted in February and March 1993, that showed that
Discovery was in violation of CGMP regulations at the time of the
inspection. Thus, the deficiencies could not have been discovered by
FDA during its review of Discovery's NDA as asserted by Discovery.
Discovery's response does not challenge the issue raised by FDA in the
NOOH. Thus, I find that Discovery's response is not probative of the
issue raised by FDA and, therefore, does not raise a genuine and
substantial issue of fact requiring a hearing (Secs. 12.24(b)(1) and
314.200(g)).
In its response to this issue, Discovery failed to distinguish
between Sec. 314.50(d)(1)(i) and (d)(1)(ii)(a), which require an NDA to
contain certain information about the manufacture and control of a new
drug substance and drug product,\16\ and Sec. 314.125(b)(13), which
permits FDA to refuse to approve an NDA if the applicant's methods,
facilities, and controls do not conform to CGMP requirements set forth
at parts 210 and 211.
---------------------------------------------------------------------------
\16\ FDA may refuse to approve an NDA that lacks such
information under Sec. 314.125(b)(1).
---------------------------------------------------------------------------
Regarding Discovery's second and third assertions, that the CGMP
violations cited in the NOOH did not exist at the time of the FDA
inspection, and that the FDA investigators did not mention the
deficiencies to Discovery at the time of the inspection, I find that
the record clearly establishes that Discovery's assertions are
incorrect.
Contrary to Discovery's assertion, it is facially evident from the
record that FDA investigators issued a Form FDA 483 (list of
observations) to Mr. James T. Kimball, President at the conclusion of
the inspection on March 2, 1993, which listed all of the above CGMP
violations. Indeed, on p. 9 of its response, Discovery admitted that it
``received the FDA's noted deficiencies.''
Moreover, Discovery admitted on p. 53 of its response that FDA
investigators ``found that most everything [Discovery] was doing was in
order, except for a couple of written GMP's [sic] that needed to be
amended.'' On p. 9 of its response, Discovery further admitted that
``[i]n fact, some of [Discovery's] procedures were above FDA standards,
but not all of these procedures were written into [Discovery's] GMP,
which is a requirement.''
Finally, Discovery did not submit any evidence that it had the
written procedures in place during the March 1993 FDA inspection.
Discovery's mere assertions that the CGMP violations did not exist, and
that none had been communicated to it during the FDA inspection, in the
face of its admissions that CGMP deficiencies did exist, and that it
had received notice of them, fail to raise a genuine and substantial
issue of fact requiring a hearing (Secs. 12.24(b)(1) and (b)(2) and
314.200(g)).
Discovery's failure to comply with CGMP is, in and of itself, a
sufficient basis upon which to refuse to approve NDA 20-242
(Sec. 314.125(b)(13)).
III. Findings and Conclusions
Based upon the above, I find that Discovery has failed to raise a
genuine and substantial issue of fact related to the approvability of
NDA 20-242 in its response to the NOOH. A hearing, therefore, is not
required.
Further, I find that NDA 20-242: (1) Fails to contain information
about Deprenyl to determine whether the product is safe for use under
the
[[Page 15914]]
conditions suggested in its proposed labeling; (2) lacks evidence
consisting of adequate and well-controlled investigations that Deprenyl
will have the effect it is represented to have in the NDA; (3) fails to
contain bioavailability data required by Sec. 320.21; (4) fails to
contain information that establishes that the methods to be used in,
and the facilities and controls used for, the manufacture, processing,
packing, or holding of the drug substance and the drug product are
adequate to preserve their identity, strength, quality, purity,
stability, and bioavailability; and (5) does not contain the proposed
labeling for the bulk drug substance and the packaged drug product. I
also find that Discovery was not in compliance with FDA's CGMP
regulations published at parts 210 and 211.
Therefore, under the Federal Food, Drug, and Cosmetic Act (section
505(d)) and under the authority delegated to me in 21 CFR 5.10,
Discovery's request for a hearing is denied and approval of NDA 20-242
is denied.
Dated: February 28, 1997.
Michael A. Friedman,
Deputy Commissioner for Operations.
[FR Doc. 97-8517 Filed 4-2-97; 8:45 am]
BILLING CODE 4160-01-F
