Federal Register / Vol. 62, No. 64 / Thursday, April 3, 1997 / Notices 15903

legislation is to impose a new duty or

burden based upon past acts (id.

(citations omitted)). The Court noted,

however, that it would ‘‘hesitate to

approve the retrospective imposition of

liability on any theory of deterrence * *

* or blameworthiness’’ (id. (citations

omitted)). Neither exception applies to

debarment.

As discussed above, debarment is

remedial, in that it prohibits certain

individuals from providing services to a

person that has an approved or pending

drug product application, in order to

meet the legitimate regulatory purpose

of restoring the integrity of the drug

approval and regulatory process and

protecting the public health. In

addition, the remedial nature of the

GDEA is not diminished simply because

the GDEA deters debarred individuals

and others from future misconduct (U.

S. v. Halper, 109 S. Ct. 1892, 1901, n.7

(1989); Bae v. Shalala, 44 F.3d 489, 493

(7th Cir. 1995)). Thus, debarment for a

1991 conviction does not violate Mr.

Elbert’s due process rights.

With regard to his ‘‘takings’’ assertion,

Mr. Elbert has not established that his

debarment affects any property interest

protected by the Fifth Amendment. The

expectation of employment is not

recognized as a protected property

interest under the Fifth Amendment

(Hoopa Valley Tribe v. Christie, 812

F.2d 1097, 1102 (9th Cir. 1986); Chang

v. United States, 859 F.2d 893, 896–897

(Fed. Cir. 1988)). One who voluntarily

enters a pervasively regulated industry,

such as the pharmaceutical industry,

and then violates its regulations, cannot

successfully claim that he has a

protected property interest when he is

no longer entitled to the benefits of that

industry (Erikson v. United States, 67

F.3d 858 (9th Cir. 1995)).

Mr. Elbert further alleges that his

debarment denies him ‘‘equal protection

of law,’’ insofar as persons other than

individuals are subject to debarment for

acts occurring after enactment of the

GDEA, and individuals are subject to

debarment for acts and convictions that

occurred prior to enactment of the

statute as well. This argument also must

fail. A statutory classification, such as

that made in the GDEA between

individuals and persons other than

individuals, that neither burdens a

fundamental right nor targets a suspect

class, will be sustained if the

classification bears a rational

relationship to a legitimate legislative

end (Romer v. Evans, 116 S. Ct. 1620,

1627 (1996)). The classification will be

upheld even if it works to the

disadvantage of a particular group (id).

Moreover, under the rational basis

standard of review, Congress need not

articulate the rationale supporting its

classification (FCC v. Beach, 113 S. Ct.

2096, 2102 (1993)). The distinction

drawn between individuals and persons

other than individuals may well have

been supported by the fact that Congress

had before it evidence from hearings

that at least one company that had been

found guilty or had admitted to fraud

had obtained new management prior to

passage of the GDEA (Generic Drug

Enforcement: Hearing on H.R. 2454

Before the Subcomm. on Health and the

Environment of the House Comm. on

Energy and Commerce, 102d Cong., 60–

61 (1991) (statement of Dee Fensterer,

President, Generic Pharmaceutical

Industry Association)).

Mr. Elbert does not dispute the fact

that he was convicted as alleged by

FDA. Under section 306(l)(1)(B) of the

act, a conviction includes a guilty plea.

The facts underlying Mr. Elbert’s

conviction are not at issue. Mr. Elbert’s

legal arguments do not create a basis for

a hearing. Accordingly, the Deputy

Commissioner for Operations denies Mr.

Elbert’s request for a hearing.

III. Findings and Order

Therefore, the Deputy Commissioner

for Operations, under section 306(a) of

the act and under authority delegated to

him (21 CFR 5.20), finds that Robert

Elbert has been convicted of a felony

under Federal law for conduct relating

to the regulation of a drug product.

As a result of the foregoing finding,

Robert Elbert is permanently debarred

from providing services in any capacity

to a person with an approved or

pending drug product application under

section 505, 507, 512, or 802 of the act

(21 U.S.C. 355, 357, 360b, or 382), or

under section 351 of the Public Health

Service Act (42 U.S.C. 262), effective

April 3, 1997 (sections 306(c)(1)(B) and

(c)(2)(A)(ii) and 201(dd) of the act (21

U.S.C. 321(dd))). Any person with an

approved or pending drug product

application who knowingly uses the

services of Mr. Elbert, in any capacity,

during his period of debarment, will be

subject to a civil money penalty (section

307(a)(6) of the act (21 U.S.C.

335b(a)(6))). If Mr. Elbert, during his

period of debarment, provides services

in any capacity to a person with an

approved or pending drug product

application, he will be subject to civil

money penalties (section 307(a)(7) of the

act). In addition, FDA will not accept or

review any ANDA or abbreviated

antibiotic drug application submitted by

or with the assistance of Mr. Elbert

during his period of debarment.

Mr. Elbert may file an application to

attempt to terminate his debarment

under section 306(d)(4) of the act. Any

such application would be reviewed

under the criteria and processes set

forth in section 306(d)(4)(C) and

(d)(4)(D) of the act. Such an application

should be identified with Docket No.

93N–0457 and sent to the Dockets

Management Branch (address above).

All such submissions are to be filed in

four copies. The public availability of

information in these submissions is

governed by 21 CFR 10.20(j). Publicly

available submissions may be seen in

the Dockets Management Branch

between 9 a.m. and 4 p.m., Monday

through Friday.

Dated: March 17, 1997.

Michael A. Friedman,

Deputy Commissioner for Operations.

[FR Doc. 97–8555 Filed 4–2–97; 8:45 am]

BILLING CODE 4160–01–F

[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.

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.
15904 Federal Register / Vol. 62, No. 64 / Thursday, April 3, 1997 / Notices

1An 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).

2Subsequent 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.

3Now codified in § 314.101(a)(3).

4On 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.

5 In its response, Discovery refers to itself by its

acronym, DEDI.

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.

In a letter dated January 17, 1992,

FDA notified Discovery that it was not

filing NDA 20–242, under § 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

§ 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.

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 § 314.101(c),3 which Discovery

requested on December 7, 1992.

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

§ 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

§ 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 § 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 § 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 § 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

I have reviewed Discovery’s

arguments and find that Discovery has

not raised a genuine and substantial

issue of fact requiring a hearing under

§§ 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.

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 (§§ 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.,

§ 314.126(c) (21 CFR 314.126(c))), the
Federal Register / Vol. 62, No. 64 / Thursday, April 3, 1997 / Notices 15905

6Even 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.

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); HoffmanLaRoche, Inc. v. Weinberger, 425 F.

Supp. 890 (D.D.C. 1975); see also,

§ 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, §§ 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 wellcontrolled studies (section 505(b) and

(d) of the act). FDA regulations in turn

identify the characteristics of a wellcontrolled 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 (§ 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 (§§ 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 (§§ 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 (§§ 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

(§§ 12.24(b)(1) and 314.200(g)). The

allegation simply is not relevant to this

proceeding.

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 (§§ 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
15906 Federal Register / Vol. 62, No. 64 / Thursday, April 3, 1997 / Notices

8Supra note 2.

which a hearing is not required

(§§ 12.24(b)(4) and 314.200(g)).

d. FDA violated § 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 Discovery8 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 § 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’’ § 314.103

in January 1992. A hearing, therefore, is

not required (§§ 12.24(b)(3) and

314.200(g)).

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 (§§ 12.24(b)(4) and 314.200(g)).

e. FDA violated § 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’’ (§ 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 § 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 (§§ 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 (§§ 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

§ 314.101(c) (now § 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 §§ 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
Federal Register / Vol. 62, No. 64 / Thursday, April 3, 1997 / Notices 15907

9See 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).

10Section 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)).

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 §§ 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 (§§ 12.24(b)(1) and

314.200(g)).

h. FDA violated § 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

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

(§§ 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

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.
15908 Federal Register / Vol. 62, No. 64 / Thursday, April 3, 1997 / Notices

11Section 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,

§ 314.125(a)(3) states that FDA may refuse to

approve an NDA for any of the reasons listed in

§ 314.125(b).

12Nonclinical studies are studies involving

animals as test subjects and are designed to

determine if the new drug is safe for use in humans.

13FDA 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).

14Somerset’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.

15Absent 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.

Section 505(d) of the act11

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 § 314.50.

In the NOOH, FDA stated that NDA

20–242 failed to contain any nonclinical

studies12 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

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

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 (§§ 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

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
Federal Register / Vol. 62, No. 64 / Thursday, April 3, 1997 / Notices 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

(§§ 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, §§ 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

(§§ 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

§ 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 (§§ 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 (§§ 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 (§ 314.126(b)(5); and copies of

case report forms or data tabulations,

and individual patient data on safety

and effectiveness measures (§§ 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 wellcontrolled 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 wellcontrolled 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
15910 Federal Register / Vol. 62, No. 64 / Thursday, April 3, 1997 / Notices

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., ‘‘LDeprenyl 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 LDeprenyl 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 wellcontrolled 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 (§§ 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

(§§ 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 (§§ 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
Federal Register / Vol. 62, No. 64 / Thursday, April 3, 1997 / Notices 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 (§§ 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 § 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 § 314.50.

A hearing, therefore, is not required

(§§ 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 § 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 (§ 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 (§§ 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 (§§ 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

§ 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 (§§ 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, §§ 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 (§§ 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.
15912 Federal Register / Vol. 62, No. 64 / Thursday, April 3, 1997 / Notices

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

(§ 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 (§§ 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 (§§ 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

(§§ 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 § 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 (§§ 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

§ 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

§§ 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

(§§ 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 (§§ 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 (§§ 12.24(b)(1) and

(b)(4) and 314.200(g)).

Discovery’s failure to include

information required by § 201.122, in

and of itself, is a sufficient basis upon

which to refuse to approve NDA 20–242

(§ 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 (§§ 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
Federal Register / Vol. 62, No. 64 / Thursday, April 3, 1997 / Notices 15913

16FDA may refuse to approve an NDA that lacks

such information under § 314.125(b)(1).

Selegiline,’’ Acta Neurologica

Scandinavia, Suppl., 136:44–59, 1990.)

In response to the NOOH, Discovery

merely asserted that,

In addition, the FDA reverts to bioequivalency, 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

(§§ 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 (§§ 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

(§ 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

(§ 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 (§ 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 (§ 211.22); (b) cleaning and

maintenance of equipment used in

manufacturing products (§ 211.67); (c)

receipt and handling of components

(§ 211.82); (d) production and process

control, e.g., weighing components

(§ 211.101); and (e) in-process controls

or testing (§ 211.110).

2. Discovery lacked a written stability

program. Additionally, Discovery could

locate no records documenting stability

testing of selegiline citrate (§ 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 (§ 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 (§§ 12.24(b)(1)

and 314.200(g)).

In its response to this issue, Discovery

failed to distinguish between

§ 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 § 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.

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 (§§ 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 (§ 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
15914 Federal Register / Vol. 62, No. 64 / Thursday, April 3, 1997 / Notices

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 § 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

Health Care Financing Administration

[HCFA–R–204]

Agency Information Collection

Activities: Proposed Collection;

Comment Request

In compliance with the requirement

of section 3506(c)(2)(A) of the

Paperwork Reduction Act of 1995, the

Health Care Financing Administration

(HCFA), Department of Health and

Human Services, is publishing the

following summary of proposed

collections for public comment.

Interested persons are invited to send

comments regarding the burden

estimate or any other aspect of this

collection of information, including any

of the following subjects: (1) The

necessity and utility of the proposed

information collection for the proper

performance of the agency’s functions;

(2) the accuracy of the estimated

burden; (3) ways to enhance the quality,

utility, and clarity of the information to

be collected; and (4) the use of

automated collection techniques or

other forms of information technology to

minimize the information collection

burden.

Type of Information Collection

Request: New Collection; Title of

Information Collection: Data Collection

for the Second Generation Social Health

Maintenance Organization

Demonstration; Form No.: HCFA–R–

204; Use: The data collected under this

effort will be used to support the

operational and evaluation needs of the

Congressionally-Mandated Second

Generation of the Social Health

Maintenance Organization

Demonstration. Frequency: On occasion,

Annually; Affected Public: Individuals

or Households; Number of Respondents:

157,056; Total Annual Responses:

157,056; Total Annual Hours: 133,652.

To obtain copies of the supporting

statement for the proposed paperwork

collections referenced above, access

HCFA’s WEB SITE ADDRESS at http://

www.hcfa.gov/regs/prdact95.htm, or to

obtain the supporting statement and any

related forms, E-mail your request,

including your address and phone

number, to Paperwork@hcfa.gov, or call

the Reports Clearance Office on (410)

786–1326. Written comments and

recommendations for the proposed

information collections must be mailed

within 60 days of this notice directly to

the HCFA Paperwork Clearance Officer

designated at the following address:

HCFA, Office of Financial and Human

Resources, Management Analysis and

Planning Staff, Attention: John Rudolph,

Room C2–26–17, 7500 Security

Boulevard, Baltimore, Maryland 21244–

1850.

Dated: March 26, 1997.

Edwin J. Glatzel,

Director, Management Analysis and Planning

Staff, Office of Financial and Human

Resources.

[FR Doc. 97–8526 Filed 4–2–97; 8:45 am]

BILLING CODE 4120–03–P

[HCFA–R–203]

Agency Information Collection

Activities: Submission for OMB

Review; Comment Request

In compliance with the requirement

of section 3506(c)(2)(A) of the

Paperwork Reduction Act of 1995, the

Health Care Financing Administration

(HCFA), Department of Health and

Human Services, has submitted to the

Office of Management and Budget

(OMB) the following proposal for the

collection of information. Interested

persons are invited to send comments

regarding the burden estimate or any

other aspect of this collection of

information, including any of the

following subjects: (1) The necessity and

utility of the proposed information

collection for the proper performance of

the agency’s functions; (2) the accuracy

of the estimated burden; (3) ways to

enhance the quality, utility, and clarity

of the information to be collected; and

(4) the use of automated collection

techniques or other forms of information

technology to minimize the information

collection burden.

Type of Information Collection

Request: New Collection; Title of

Information Collection: Data Collection

Forms for a Project to Develop a CaseMix Adjustment System for a National

Home Health Prospective Payment

Program; Form No.: HCFA–R–203; Use:

The data collection from this form will

support analysis of home health

utilization patterns and develop

predictive models of home health

resource use. That will serve as the basis

for a system to adjust payments for

Medicare home health services for

differences/changes in patient service

needs; Frequency: On Occasion;

Affected Public: Not-for-profit, Business

or other for-profit; Number of

Respondents: 893,629; Total Annual

Responses: 893,629; Total Annual

Hours: 52,156.

To obtain copies of the supporting

statement for the proposed paperwork

collections referenced above, access

HCFA’s WEB SITE ADDRESS at http://

www.hcfa.gov/regs/prdact95.htm, or to

obtain the supporting statement and any

related forms, E-mail your request,

including your address and phone

number, to Paperwork@hcfa.gov, or call

the Reports Clearance Office on (410)

786–1326. Written comments and

recommendations for the proposed

information collections must be mailed

within 30 days of this notice directly to

the HCFA Paperwork Clearance Officer

designated at the following address:

OMB Human Resources and Housing

Branch, Attention: Allison Eydt, New

Executive Office Building, Room 10235,

Washington, D.C. 20503.

Dated: March 11, 1997.

Edwin J. Glatzel,

Director, Management Analysis and Planning

Staff, Office of Financial and Human

Resources, Health Care Financing

Administration.

[FR Doc. 97–8525 Filed 4–2–97; 8:45 am]

BILLING CODE 4120–03–P

Health Resources and Services

Administration

Agency Information Collection

Activities: Proposed Collection:

Comment Request

In compliance with the requirement

for opportunity for public comment on

proposed data collection projects

(section 3506(c)(2)(A) of Title 35, United

States Code, as amended by the