Discovery Experimental and Development, Inc.; Deprenyl Gelatin Capsules and Liquid (Deprenyl Citrate); Proposal to Refuse to Approve a New Drug Application; Opportunity for a Hearing

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 94N-0171]

Discovery Experimental and Development, Inc.; Deprenyl Gelatin

Capsules and Liquid (Deprenyl Citrate); Proposal to Refuse to Approve a

New Drug Application; Opportunity for a Hearing

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) proposes to disapprove

a new drug application (NDA) for Deprenyl (deprenyl citrate or

deprenyl), submitted by Discovery Experimental and Development, Inc.,

29949 S.R. 54 West, Wesley Chapel, FL 33543 (Discovery). FDA is also

providing Discovery notice of an opportunity for a hearing on the

proposal. The grounds for FDA's proposed refusal to approve are

numerous. Most importantly, FDA concludes that 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. Discovery's deprenyl citrate is intended for the

treatment of Alzheimer's disease.

DATES: A hearing request is due on or before June 30, 1994; data and

information in support of the hearing request are due on or before July

18, 1994.

ADDRESSES: A request for hearing, supporting data, and other comments

are to be identified with Docket No. 94N-0171 and submitted to the

Dockets Management Branch (HFA-305), Food and Drug Administration, rm.

1-23, 12420 Parklawn Dr., Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Megan L. Foster, Center for Drug

Evaluation and Research (HFD-366), Food and Drug Administration, 7500

Standish Pl., Rockville, MD 20855, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

Discovery has submitted an NDA for deprenyl citrate with proposed

labeling for the treatment of Alzheimer's disease. Throughout most of

this document, the drug product is referred to as deprenyl citrate or

deprenyl. Occasionally, especially when referring to the active drug

substance, the term selegiline is used to be consistent with terms and

claims made in the NDA. An NDA for another deprenyl product, selegiline

hydrochloride (Eldepryl) held by Somerset Pharmaceuticals,

Inc. (Somerset), was approved on June 5, 1989, for the treatment of

Parkinson's disease. The Somerset product, l-deprenyl, is the

levorotatory acetylenic derivative of phenethylamine.

Discovery claims that there are:

``four distinct functions of deprenyl in helping curb or delay

the effects of Alzheimer's disease, and could very well delay the

onset of disease, if taken as a preventative.

Function 1. Deprenyl causes the body to naturally produce more

dopamine, which normally depletes with age, which, in turn, assists

in maintaining healthy brain cells.

Function 2. Deprenyl blocks toxic free radicals from breaking

down dopamine, which causes further degeneration of brain cells.

Function 3. Deprenyl revives malfunctioning and dormant brain

cells, bringing back lost body functions.

Function 4. Deprenyl increases the body's hormone content, which

improves the body's motorability and the immune system * * *.''

On November 29, 1991, Discovery submitted NDA 20-242 with data and

information intended to demonstrate deprenyl citrate's safety and

effectiveness in the treatment of Alzheimer's disease and proposed that

the product be marketed without prescription. Discovery submitted a

minor amendment on December 6, 1991, providing an updated table of

contents and some revised pages in the NDA.

On January 17, 1992, FDA notified Discovery by letter that the NDA

was not acceptable for filing under 21 CFR 314.101 because the NDA was

not sufficiently complete to permit a substantive review. FDA described

numerous deficiencies in an attachment to the letter.

In response to FDA's refusal to file, Discovery requested an

informal conference with FDA, and this was held on November 16, 1992.

In a letter to Discovery dated November 24, 1992, FDA notified

Discovery of its option to amend its application under 21 CFR

314.101(a)(3) and file it over protest, and Discovery did this on

December 7, 1992.

In a letter dated December 31, 1992, FDA acknowledged Discovery's

request to file over protest and stated that the application would be

reviewed as filed. (In a letter dated February 9, 1993, Discovery

objected to the advice given in FDA's letters of November 24, and

December 31, 1992, that an NDA filed over protest may not be amended

once filed.)

In a letter to Discovery dated August 20, 1993, FDA concluded that

the information presented by Discovery was inadequate and that the

application was not approvable (21 CFR 314.120). Discovery responded

with a letter dated September 1, 1993, requesting a time extension of

180 days, under 21 CFR 314.120(a)(5), to consider its options regarding

its application. FDA granted this request. In a letter dated March 1,

1994, and received by FDA March 7, 1994, Discovery requested the

opportunity for a hearing under 21 CFR 314.120(a)(3) on the question of

whether there are grounds for denying approval of NDA 20-242.

II. The Deficiencies in NDA 20-242

Discovery is required to submit, among other things, ``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,'' under

section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act (the act)

(21 U.S.C. 355(b)(1)), as well as all information required under 21 CFR

314.50.

Discovery's NDA 20-242 provides insufficient information to

determine whether Deprenyl gelatin capsules and liquid are safe, and

fails to include adequate tests by all methods reasonably applicable to

show whether or not Deprenyl gelatin capsules and liquid are safe; the

NDA lacks substantial evidence that Deprenyl gelatin capsules and

liquid will have the effect they are represented to have; and the

methods used in, and facilities and controls used for, the manufacture,

processing, and packing of Deprenyl gelatin capsules and liquid are

inadequate to preserve their identity, strength, quality, and purity

(section 505(d) of the act). In addition, Discovery's NDA 20-242 fails

to include an adequate environmental assessment, fails to include

proper labeling and bioavailability data, and fails to demonstrate

compliance with current good manufacturing practice regulations. A

detailed description of these deficiencies follows.

A. The Safety of Deprenyl

Under section 505(d) of the act and 21 CFR 314.125(b)(2) and

(b)(4), Discovery fails to include in NDA 20-242 adequate tests by all

methods reasonably applicable to show whether or not Deprenyl gelatin

capsules and liquid are safe for use under the conditions prescribed,

recommended, or suggested in the proposed labeling, and sufficient

information about Deprenyl gelatin capsules and liquid to determine

whether they are safe for use under the conditions prescribed,

recommended, or suggested in the proposed labeling.

1. Preclinical Data

Discovery fails to include either reports of the complete range of

studies necessary to assess the pharmacological and toxicological

profile of the drug (21 CFR 314.50(d)) or clinical data to obviate the

need for such studies.

Discovery fails to include any of the required toxicology studies

such as: (1) Acute and subacute studies in rodents and nonrodents, (2)

chronic studies consisting of a 6-month rodent and a 12-month nonrodent

study, (3) a genotoxicity screen, (4) studies that examine the effects

of the drug on reproduction, and (5) carcinogenicity studies (21 CFR

314.50(d)(2)). Examples of the types of material FDA would review are

described in ``Guideline for the Format and Content of the Nonclinical/

Pharmacology/Toxicology Section of an Application.''

2. Clinical Data

As noted above, selegiline hydrochloride (l-deprenyl) is currently

being marketed as Eldepryl by Somerset for the treatment of

Parkinson's disease. The exclusivity period for this application

expires on June 6, 1994. FDA could only review NDA 20-242 as an

application submitted under section 505(b)(1) of the act because until

the exclusivity period of Eldepryl expires, no application

submitted under section 505(b)(2) or section 505(j) of the act which

refers to Eldepryl can be approved.

In NDA 20-242, Discovery attempts to use the previous approval of

Somerset's selegiline hydrochloride product as evidence of the safety

of its deprenyl citrate product. The mere fact of approval may not,

however, be used in this way. Section 505(b)(1) of the act requires

that Discovery submit full reports of investigations that have been

made to show its product is safe. Safety studies of Eldepryl

are not available to Discovery for use in satisfying this requirement.

Moreover, if Discovery's claims that Deprenyl is ``purer, more potent

and more effective'' than Eldepryl are true, such differences

could reflect, among other things, increased absorption or rate of

absorption, with increased concentration in, or rate of transmission of

the drug into the brain, and a greater potential for adverse events. In

NDA 20-242, no safety study was performed using Discovery's product and

there was no study comparing the bioavailability of Discovery's product

to Eldepryl. Accordingly, FDA cannot assess its safety.

B. The Effectiveness of Deprenyl

Under section 505(d) of the act and 21 CFR 314.125(b)(5), Discovery

has failed to provide in NDA 20-242 substantial evidence, consisting of

adequate and well-controlled studies, that Deprenyl gelatin capsules

and liquid will have the effect they are represented to have under the

conditions of use prescribed, recommended, or suggested in their

proposed labeling.

The proposed labeling in Discovery's application claims that

deprenyl citrate demonstrates a ``quantitative and qualitative

improvement in cognitive functions of Alzheimer's patients as a result

of the inhibition of MAO-B activity.'' To support this claim, Discovery

includes reprints from 171 articles in the medical and scientific

literature. Although some of these articles pertain to deprenyl, not

one study used Discovery's product or a product with a known

bioavailability relationship to Discovery's product.

Discovery identified 12 of these 171 articles as evidence of the

effectiveness of deprenyl citrate in the treatment of Alzheimer's

disease. This notice discusses the first of these articles in greater

detail than the others because it has many characteristics of a well-

controlled study and, if the report submitted were supplemented with

additional information, it might qualify as an adequate and well-

controlled study supporting the effectiveness of a deprenyl drug

product in the treatment of Alzheimer's disease. The remaining 11

studies are inherently incapable of being regarded as substantial

evidence of the effectiveness of deprenyl citrate in the treatment of

Alzheimer's disease; these are therefore summarized only briefly below.

1. Mangoni, A., et al., ``Effects of a MAO-B Inhibitor in the

Treatment of Alzheimer Disease,'' European Neurology, 31:100-107, 1991.

i. Design. One hundred thirty-six patients with mild to moderate

Alzheimer-type disorders were enrolled in a 3-month randomized, double-

blind, placebo-controlled trial. They were evaluated at baseline and

months 1, 2, and 3. Of the enrolled patients, 17 dropped out following

randomization and before the first effectiveness assessment (the

article does not report the number from each group, but if original

randomization created two groups of approximately equal size, i.e., 68

in each group, then, based on the number remaining in each group at the

end of the study, virtually all 17 drop-outs would seem to have been

from the placebo group). Seven more (three on deprenyl and four on

placebo) did not complete 3 months of therapy. No explanation is given

for the 17 early drop-outs or for the apparent imbalance in them. The

seven later patients were discontinued for poor efficacy (two deprenyl

patients, four placebo patients) or poor compliance (one deprenyl

patient). There was thus an imbalance in the number of patients treated

and analyzed: 65 L-deprenyl (10 milligrams per day) and 47 placebo

patients were included in the final analysis of effectiveness.

Effectiveness measurements were conducted in the following prefixed

sequence: (1) Blessed's Dementia Scale, (2) digit span (Wechsler Memory

Scale (WMS)), (3) Raskin and Crook's Inventory of Psychic and Somatic

Complaints for the Elderly, (4) short story (WMS)--immediate recall,

(5) simple copy of drawings, (6) Toulouse-Pieron attention test, (7)

facilitated copy of drawings, (8) short story (WMS)--delayed recall,

and (9) word fluency. Measurements were taken at baseline, and at the

end of the first second, and third months.

ii. Results. Based on an analysis of variance between treatments

including all four test occasions, statistically significant

differences are reported favoring L-deprenyl over placebo on all

measurements except one portion of the Toulouse-Pieron attention test.

iii. Discussion. Taken at face value, the results in this published

study suggest a positive effect of L-deprenyl in patients with

Alzheimer's disease. However, the published report lacks many of the

details needed to assess a study. Thus, this study, as published and

without additional information, cannot contribute to fulfilling the

statutory requirement for substantial evidence of effectiveness:

(a) Discovery has failed to provide data from a bioequivalence

study demonstrating that the rate and extent of absorption of its

product is essentially identical to the product manufactured by Chiesi

Farmaceutici S.p.A. (Parma, Italy) used in the Mangoni study (21 CFR

320.21 and 314.126(d)).

(b) No protocol is available for review to determine if the design

and analysis, including analysis of patients not completing the study,

were performed as proposed (21 CFR 314.50 and 314.126(b)(1)).

(c) Measures and specific procedures to minimize bias (e.g.,

details of randomization, blinding, maintenance of patient assignment

code) are not described, and no explanation for the large imbalance in

initial dropouts is given (21 CFR 314.126(b)(5)).

(d) Case report forms or data tabulations, and individual patient

data on safety and effectiveness measures are not provided (21 CFR

314.50 and 314.126(a)).

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 is not an adequate and

well-controlled clinical study of the effectiveness of deprenyl citrate

in the treatment of Alzheimer's disease; it is a study in rats, not a

clinical study (21 U.S.C. 355(d); see 21 CFR 314.126, passim).

3. Heinonen, E. H., et al., ``Pharmacokinetics and Metabolism of

Selegiline,'' Acta Neurologica Scandinavia, 126:93-99, 1989. This study

is not an adequate and well-controlled clinical study of the

effectiveness of deprenyl citrate in the treatment of Alzheimer's

disease; the clear objective of this study was to study the

pharmacokinetics, not the effectiveness, of selegiline (deprenyl) (21

U.S.C. 355(d); see 21 CFR 314.126, passim).

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 is not an adequate and well-controlled clinical study of the

effectiveness of deprenyl citrate in the treatment of Alzheimer's

disease; it was a study of Parkinson's, not Alzheimer's, disease (see,

e.g., 21 CFR 314.126(b)(6)).

5.Tariot, P. N., et al., ``Cognitive Effects of L-Deprenyl in

Alzheimer's Disease,'' Psychopharmacology, 91:489-495, 1987. This

allegedly double-blind study in 17 patients is not an adequate and

well-controlled clinical study of the effectiveness of deprenyl citrate

in the treatment of Alzheimer's disease. There is no protocol available

to provide details (21 CFR 314.126(b)(1)). Despite the lack of a

protocol, it is clear that the study did not use a randomized

concurrent control (21 CFR 314.126(b)(2)) or other means of assuring

comparability of treatment and control groups (21 CFR 314.126(b)(3)).

Procedures to minimize bias, such as blinding are not described (21 CFR

314.126(b)(5)), and the test drug is not identified (21 CFR

314.126(d)).

6. Tariot, P. N., et al., ``L-Deprenyl in Alzheimer's Disease:

Preliminary Evidence for Behavioral Change with Monoamine Oxidase B

Inhibition,'' Archives of General Psychiatry, 44:427-433, 1987. (This

is a preliminary report of the data from the Tariot study described

immediately above.)

7. Tariot, P. N., et al., ``Tranylcypromine Compared with L-

Deprenyl in Alzheimer's Disease,'' Journal of Clinical Psycho-

pharmacology, 8:23-27, 1988. This seven-patient study is not an

adequate and well-controlled clinical study of the effectiveness of

deprenyl citrate in the treatment of Alzheimer's disease; its primary

purpose was to investigate tranylcypromine, a drug of unknown

effectiveness in the treatment of Alzheimer's disease (see, e.g., 21

CFR 314.126(b)(2)(iv)).

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 is not an adequate and

well-controlled clinical study of the effectiveness of deprenyl citrate

in the treatment of Alzheimer's disease; the clear objective of this

study was to study the pharmacokinetics, not the effectiveness, of

deprenyl (21 U.S.C. 355(d); see 21 CFR 314.126, passim).

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 is not an adequate and well-controlled clinical

study of the effectiveness of deprenyl citrate in the treatment of

Alzheimer's disease; its primary purpose was the study of the effects

in certain tissues of hydrogen peroxide, not deprenyl citrate, and it

is not a clinical study, i.e., a study in human patients with the

disease intended to be treated (21 U.S.C. 355(d); see 21 CFR 314.126,

passim).

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 is not an adequate and well-controlled clinical study of the

effectiveness of deprenyl citrate in the treatment of Alzheimer's

disease; it is not the report of an investigation, and moreover, does

not even mention deprenyl or selegiline (21 U.S.C. 355(d); see 21 CFR

314.126, passim).

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 is not an adequate and well-controlled clinical study of the

effectiveness of deprenyl citrate in the treatment of Alzheimer's

disease because it is not the report of an investigation (21 U.S.C.

355(d); see 21 CFR 314.126, passim).

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 is not an adequate and

well-controlled clinical study of the effectiveness of deprenyl citrate

in the treatment of Alzheimer's disease because, inter alia, it is not

the report of an investigation that permits a valid comparison with a

control (21 CFR 314.126(b)(2)).

C. Methods, Facilities, and Controls used by Discovery

Discovery's application is not approvable under section 505(d) of

the act and 21 CFR 314.125(b)(1). 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 are inadequate

to preserve its identity, strength, quality, purity, stability, and

bioavailability.

1. Drug Substance

The application fails to contain adequate information concerning

the methods used in the synthesis, extraction, isolation, or

purification of the new drug substance to determine its identity,

strength, quality, and purity. The many items of information required

under 21 CFR 314.50(d)(1) that are absent from NDA 20-242 include, but

are not limited to, the following:

i. A full description of the physical and chemical characteristics

of the drug substance, including adequate proof of structure and

stereochemistry. This characterization should be for the selegiline

base and citrate (claimed by the applicant to be a unique drug

substance), and should include elemental analysis, infra-red

spectroscopy, ultraviolet spectroscopy, 1H and 13C nuclear magnetic

resonance (suitable to determine characterization from coupling, peak

positions, and peak patterns), a specific identity test for citrate and

a suitable study to demonstrate that a 1:1 citrate salt has actually

been formed. Examples of the types of material FDA would review are

described in ``Guideline for Submitting Supporting Documentation in

Drug Applications for the Manufacture of Drug Substances,'' pp. 3-5. In

addition, the NDA does not include all physical data for the selegiline

citrate and a certificate of analysis with completed tests for all

proposed specifications. Examples of the types of material FDA would

review are described in ``Guideline for Submitting Samples and

Analytical Data for Methods Validation,'' p. 5.

ii. An adequate description of the method of synthesis. The

application lacks manufacturing procedures or master batch formulas

with quantities. Examples of the types of material FDA would review are

described in ``Guideline for Submitting Supporting Documentation in

Drug Applications for the Manufacture of Drug Substances,'' e.g., pp.

11-18. Discovery's argument that its manufacture of the selegiline base

was a patented process that expired in 1985 does not obviate the need

for Discovery to submit complete manufacturing information. This

information is required regardless of whether or not the patent

expired.

iii. A list of in-process controls describing the methods used to

determine the completion of each reaction. Examples of the types of

material FDA would review are described in ``Guideline for Submitting

Supporting Documentation in Drug Applications for the Manufacture of

Drug Substances,'' pp. 29-36.

iv. A description of the reagents, solvents, and materials used in

the synthesis of the drug substance. Examples of the types of material

FDA would review are described in ``Guideline for Submitting Supporting

Documentation in Drug Applications for the Manufacture of Drug

Substances,'' p. 10.

v. A description of the container closure system for storage and

shipping of the drug substance. The application does not provide the

name of the manufacturer for each component or a letter of

authorization to the manufacturer's drug master file. Examples of the

types of material FDA would review are described in ``Guideline for the

Format and Content of the Chemistry, Manufacturing, and Controls

Section of an Application,'' pp. 4-5. See also, 21 CFR 314.420(b).

2. Drug Product

i. Components, composition, and formulation. The application does

not identify by established name, if any, or complete chemical name,

each of the substances used as components of the drug product including

each substance used in the synthesis, extraction, or other method of

preparation of the new drug substance. The specific areas of

information pertaining to drug product components, composition, and

formulation required by 21 CFR 314.50(d)(1)(ii) that are absent from

NDA 20-242 include the following: (1) A list of all components used in

the manufacture of the drug product, (2) a statement of the composition

of the drug product, and (3) a statement of the specifications and

analytical methods for each component.

It is even unclear from the application what dosage form Discovery

intends to manufacture. Tests absent from the application include a

specific identity test, a chiral identity test, a chiral purity test,

an assay for the drug substance, and a dissolution test. Such tests are

necessary to permit FDA to make an assessment of the drug product.

ii. Drug product manufacture. The application fails to contain a

description of the manufacturing and packaging procedure and in-process

control for the drug product. Also absent is the method of sampling for

quality assurance. (21 CFR 314.50(d)(1)(ii)). Examples of the types of

material FDA would review are described in ``Guideline for Submitting

Documentation for the Manufacture of and Controls for Drug Products,''

pp. 4-7.

iii. Drug product laboratory methods. The application fails to

include specifications and analytical methods as are necessary to

assure identity, strength, quality, and purity of the drug product (21

CFR 314.50(d)(1)(ii)), and in particular fails to include a full

description of the laboratory methods that will be used to check each

lot of the finished drug product. Sampling methods, procedures, and a

rationale for the sampling plan are not provided, and the regulatory

specifications and test methods for the drug product are also not

provided. Examples of the types of material FDA would review are

described in ``Guideline for Submitting Documentation for the

Manufacture of and Controls for Drug Products,'' pp. 7-8.

iv. Drug product container system, packaging, and controls. The

application fails to provide adequate information with respect to the

characteristics of, and the test methods employed for, the container,

closure, or other component parts of the drug package to assure their

suitability for the intended use. A description of the packaging

procedures and in-process controls for the drug product are not

included, and the container/closure system used for the drug product is

not even described (21 CFR 314.50(d)(1)(ii)). Examples of the types of

material FDA would review are described in ``Guideline for Submitting

Documentation for Packaging for Human Drugs and Biologics.''

3. Methods Validation

Discovery's application fails to include adequate laboratory test

procedures to assure that the finished drug product (or drug substance)

conforms to appropriate standards of identity, strength, quality, and

purity. Validations of the test methods were not performed. Actual

samples and full information pertaining to the samples were not

submitted to the NDA at the time of application (21 CFR 314.50(d)(1)(i)

and (ii). Examples of the types of material FDA would review are

described in ``Guideline for Submitting Samples and Analytical data for

Methods Validation.''

4. Reference Standard

The application lacks information about the reference standard and

a sample of this standard for the active ingredient, claimed to be

selegiline citrate or selegiline base. It is necessary that the

physical and chemical properties of the reference standard be described

to ensure its integrity to serve as such (21 CFR 314.50(e)(1)(i)(c)).

Examples of the types of material FDA would review are described in

``Guideline for Submitting Samples and Analytical Data for Methods

Validation,'' p. 6.)

5. Stability

The application fails to include a full description of, and data

derived from, studies of the stability of the drug. The stability of

the drug product is not demonstrated in the container closure system

proposed for use (21 CFR 314.50(d)(1)(ii); see also 21 CFR 211.166.)

Examples of the types of material FDA would review are described in

``Guideline for Submitting Documentation for the Stability of Human

Drugs and Biologics.''

6. Establishment Locations

The application fails to identify and show the location of each

establishment conducting a part of the manufacturing, processing,

packaging, and labeling operations (21 CFR 314.50(d)(1)(i) and

(d)(1)(ii)). Examples of the types of material FDA would review are

described in ``Guideline for Submitting Documentation for the

Manufacture of and Controls for Drug Products,'' p. 4. The application

lacks a clear delineation of the operations that will be performed by

persons other than Discovery. For example, the contract facility used

for encapsulation of the drug substance solution is not identified in

the submission.

7. Environmental Assessment

A complete and satisfactory environmental assessment is required

under 21 CFR 25.22(a)(14) and 314.50(d)(1)(iii), and failure to submit

an adequate environmental assessment is grounds for FDA's refusal to

approve an NDA (21 CFR 25.22(b)). An NDA must contain either a claim

for categorical exclusion under 21 CFR 25.24 or an environmental

assessment under 21 CFR 25.31a. Discovery's environmental assessment

was not a claim for exclusion, and consisted of a one paragraph

statement that is facially unresponsive to the requirements of 21 CFR

25.31a. For example, the environmental assessment in NDA 20-242 does

not provide an identification of chemical substances that are the

subject of the proposed action.

D. The Labeling of Deprenyl

The application is not approvable under section 505(d) of the act,

as well as 21 CFR 314.125(b)(8), because the proposed labeling does not

comply with requirements for labels and labeling set forth in 21 CFR

Part 201 and 21 CFR 314.50. The proposed labeling fails to meet the

statutory and regulatory requirements in numerous ways, including, but

not limited to, the following:

1. Labeling to be used for the packaged drug product is not

provided in the application (21 CFR 314.50(e)(2)(ii)).

2. Labeling to be used for shipment and storage of the bulk drug

substance (see 21 CFR 201.122), as well as all labeling required to

demonstrate compliance with current good manufacturing practice (CGMP)

regulations (see, e.g., 21 CFR 211.122), are not provided in the

application.

3. The proprietary name or designation of the drug product is not

properly accompanied by the proper established name of the drug

substance in the label or labeling of the drug product (21 CFR

201.10(g)(1)). Furthermore, the name ``deprenyl'' (as the base,

hydrochloride, or citrate salt) is not acceptable as the established

name of the drug (see 21 CFR 299.4).

E. The Bioavailability or Bioequivalence of Deprenyl

The application is not approvable under section 505(d) of the act

and 21 CFR 314.125(b)(9) because it does not contain bioavailability or

bioequivalence data required under 21 CFR part 320. The application

must contain either of the following: (1) Evidence demonstrating the in

vivo bioavailability of the drug product or (2) information which would

permit the agency to waive demonstration of in vivo bioavailability.

Discovery submitted neither and therefore has not fulfilled the

requirements for the human pharmacokinetics and bioavailability section

of the NDA as required by 21 CFR 314.50(d)(3) and 320.21(a).

Discovery contends that it is 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.'' This contention is incorrect, as shown in two articles that

provide information on metabolites. (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 Selegiline,'' Acta Neurologica Scandinavia, Suppl.,

136:44-59, 1990.)

Discovery also states in the application that ``[d]ue to the

stereospecificity and low [cerebrospinal fluid] concentration of the L-

amphetamine metabolites recovered during this trial, these metabolites

do not contribute to the clinical efficacy of deprenyl, nor do they

pose any risk to the patient after extended use.'' This statement is

not substantiated in Discovery's application and, while taken in part

from an earlier article by Heinonen (Heinonen, E. H., et al.,

``Pharmacokinetics and Metabolism of Selegiline,'' Acta Neurologica

Scandinavia, 126:93-99, 1989) is at odds with the information described

in the 1990 article by Heinonen which, states that desmethylselegiline

may contribute to the pharmacological activity during selegiline

treatment.

F. Discovery's Compliance with CGMP's

The application is not approvable under section 505(d) of the act

and 21 CFR 314.125(b)(13) because the methods to be used in, and the

facilities and controls used for, the manufacture, processing, packing,

and holding of the drug substance and drug product do not comply with

the CGMP regulations (21 CFR parts 210 and 211).

Between February 25 and March 2, 1993, FDA investigators made an

inspection of Discovery's establishment in Wesley Chapel, FL, and

observed numerous violations of the CGMP regulations. The following are

among numerous CGMP violations observed during the February through

March, 1993, inspection:

1. Discovery lacks adequate standard operating procedures with

regard to: (i) Responsibilities of the quality control unit (21 CFR

211.22); (ii) cleaning and maintenance of equipment used in

manufacturing products (21 CFR 211.67); (iii) receipt and handling of

components (21 CFR 211.82); (iv) production and process control, e.g.,

weighing components (21 CFR 211.101); (v) in-process controls or

testing (21 CFR 211.110).

2. Discovery lacks a written stability program. Additionally,

Discovery could locate no records documenting stability testing of

selegiline citrate (21 CFR 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 (21 CFR 211.188).

Until it can be verified in a subsequent inspection that Discovery

is operating in compliance with the CGMP regulations in 21 CFR parts

210 and 211, the agency cannot conclude that the methods, facilities,

and controls used for the production of the proposed drug product(s)

are adequate to assure the identity, strength, quality, and purity of

the drug product.

G. Conclusion

FDA proposes to refuse to approve Discovery's NDA 20-242 on the

grounds that Discovery has failed to provide adequate evidence of

safety, effectiveness, proper methods, facilities and controls,

environmental assessment, proper labeling, bioavailability data, and

compliance with CGMP regulations. Discovery has failed to submit the

appropriate studies and information necessary for the approval of its

product.

III. Notice of Opportunity for a Hearing

The Director of the Center for Drug Evaluation and Research (the

Director) has evaluated the information discussed above and, on the

grounds stated, is proposing to refuse to approve NDA 20-242.

Therefore, notice is given to Discovery and to all other interested

persons that the Director proposes to issue an order under section

505(d) of the act, refusing to approve NDA 20-242. The Director finds

that, (1) the investigations, reports of which are required to be

submitted pursuant to 21 U.S.C. 355(b), do not include adequate tests

by all methods reasonably applicable to show whether or not Discovery's

deprenyl citrate product is safe for use under the conditions

prescribed, recommended, or suggested in the proposed labeling thereof;

(2) the results of such tests do not show that Discovery's deprenyl

citrate product is safe for use under such conditions; (3) the methods

used in, and the facilities and controls used for, the manufacture,

processing, and packaging of Discovery's deprenyl citrate product are

inadequate to preserve its identity, strength, quality, and purity; (4)

upon the basis of the information submitted to the Director as part of

the application, and upon the basis of any other information before the

Director with respect to Discovery's deprenyl citrate product, the

Director has insufficient information to determine whether Discovery's

deprenyl citrate product is safe for use under such conditions; (5)

evaluated on the basis of the information submitted to the Director as

part of the application and any other information before the Director

with respect to Discovery's deprenyl citrate product, there is a lack

of substantial evidence that the drug will have the effect it purports

or is represented to have under the conditions or use prescribed,

recommended, or suggested in the proposed labeling thereof; and (6)

based on a fair evaluation of all material facts, the proposed labeling

is false and misleading.

In accordance with section 505 of the act and 21 CFR part 314, the

applicant is hereby given an opportunity for a hearing to show that

approval of the NDA should not be refused.

An applicant who decides to seek a hearing shall file: (1) On or

before June 20, 1994, a written notice of appearance and request for

hearing, and (2) on or before July 18, 1994, the data, information, and

analyses relied on to demonstrate that there is a genuine issue of

material fact to justify a hearing, as specified in 21 CFR 314.200. Any

other interested person may also submit comments on this notice. The

procedures and requirements governing this notice of opportunity for a

hearing, a notice of appearance and request for a hearing, information

and analyses to justify a hearing, other comments, and a grant or

denial of a hearing are contained in 21 CFR 314.200 and in 21 CFR part

12.

The failure of the applicant to file a timely written notice of

appearance and request for hearing, as required by 21 CFR 314.200,

constitutes an election by that person not to use the opportunity for a

hearing concerning the proposed action, and a waiver of any contentions

concerning the legal status of that person's drug products. Any new

drug product marketed without an approved NDA is subject to regulatory

action at any time.

A request for a hearing may not rest upon mere allegations or

denials, but must present specific facts showing that there is a

genuine and substantial issue of fact that requires a hearing. If it

conclusively appears from the face of the data, information, and

factual analyses in the request for a hearing that there is no genuine

and substantial issue of fact that precludes the refusal to approve the

application, or when a request for hearing is not made in the required

format or with the required analyses, the Commissioner of Food and

Drugs will enter summary judgment against the person who requests the

hearing, making findings and conclusions, and denying a hearing.

All submissions pursuant to this notice of opportunity for a

hearing are to be filed in four copies. Except for data and information

prohibited from public disclosure under 21 U.S.C. 331(j) or 18 U.S.C.

1905, the submissions may be seen in the Dockets Management Branch

(address above) between 9 a.m. and 4 p.m., Monday through Friday.

This notice is issued under the Federal Food, Drug, and Cosmetic

Act (sec. 505 (21 U.S.C. 355)) and under authority delegated to the

Director of the Center for Drug Evaluation and Research (21 CFR 5.82).

Dated: May 5, 1994.

Murray M. Lumpkin,

Acting Director, Center for Drug Evaluation and Research.

[FR Doc. 94-12196 Filed 5-18-94; 8:45 am]

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