[Federal Register Volume 59, Number 96 (Thursday, May 19, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-12196]


[[Page Unknown]]

[Federal Register: May 19, 1994]


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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]
BILLING CODE 4160-01-F