[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
