The New Drug
Approval Requirement
Daniel R. Dwyer
Stacy L. Ehrlich
Kleinfeld, Kaplan & Becker LLP
June 14, 2004
1
What does FDA regulate?
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Drugs
Devices
Biologics
Foods
Dietary Supplements
Cosmetics
Combination Products
2
What is a Drug?
Section 201(g)(1):
 Recognized in USP or other compendia
 Intended to diagnose, cure, mitigate, treat
or prevent disease
 Intended to affect structure or function
 Intended as component of these
 Exceptions for foods and supplements
3
Intended Use
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21 CFR 201.128
Objective intent of persons
responsible for labeling of product
Based on, e.g.:
• Labeling claims
• Advertising/promotion
• Oral or written statements
• Circumstances surrounding distribution
• Consumer expectations/use?
4
What is a Device?
Section 201(h)
 Instrument, apparatus, implement,
machine, contrivance, implant, in vitro
reagent, or component
• Recognized in USP or other compendia
• Intended for use in diagnosis of disease or
other conditions
• Intended for use in the cure, mitigation,
treatment, or prevention of disease
• Intended to affect structure or function
5
Drug vs Device
Device definition excludes:
 Products that achieve their primary
intended purpose through chemical
action within or on the body
 Products that are dependent upon
being metabolized for the
achievement of their primary
intended purpose
6
Drug or Device?
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Sunscreen?
Microbubble ultrasound contrast
agents?
Injectable lubricants?
Contact lens solution?
7
What is a Biologic?
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Section 351 of PHS Act, 21 CFR
600.3(h)
Virus, therapeutic serum, toxin,
antitoxin, vaccine, blood, blood
component or derivative, allergenic
Or any analogous product
Applicable to the prevention,
treatment or cure of disease or
condition
8
Drug vs Biologic
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Definitions not mutually exclusive
Large molecules vs small molecules
Hormones, e.g., insulin and human growth
hormone, regulated as drugs
Intercenter agreements between CDER,
CBER and CDRH
Transfer of review responsibilities for most
therapeutic biologics from CBER to CDER
(except vaccines, blood products and gene
and tissue/cellular product therapies)
9
Combination Products
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Section 503(g), 21 CFR Part 3 (RFD)
MDUFMA required establishment of Office
of Combination Products
“Primary mode of action” = “the single
mode of action of a combination product
that provides the most important
therapeutic action of the combination
product” (May 7, 2004 proposed rule)
Assignment algorithm: PMOA, consistency,
safety and effectiveness expertise
10
What is a Food?
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Section 201(f) = used for food or
drink, chewing gum, components
Structure/function claims based on
“nutritive value”
Prior authorization for diseaserelated health claims
11
What is a Dietary Supplement?
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DSHEA, Section 201(ff)
Product (other than tobacco)
intended to supplement the diet that
contains vitamin, mineral,
herb/botanical, amino acid, dietary
substance, or concentrate,
metabolite, constituent or extract
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What is a Dietary Supplement?
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Prior authorization for diseaserelated health claims
Cannot be represented as a
conventional food
Cannot contain ingredient approved
or authorized for investigation as
new drug prior to marketing as food
or supplement
Can make structure/function claims
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Drug vs Dietary Supplement
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Reduces inflammation
Improves absentmindedness
Maintains cholesterol levels already in the
normal range
CarpalHealth
Supports the body’s ability to resist
infection
Helps maintain intestinal flora
For relief of occasional constipation
Dietary support during the cold and flu
season
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Drug vs Dietary Supplement
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Pharmanex case
Street drug alternatives
OTC drug-supplement
•Combination (Melagesic PM)
•Dual use (Tums)
15
What is a Cosmetic?
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Section 201(i)
Rubbed, poured, sprinkled, or
sprayed on, introduced into, or
otherwise applied to the body
For cleansing, beautifying, promoting
attractiveness, or altering
appearance
Except soap
16
Cosmetic vs Drug
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Wrinkle and anti-aging products
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Face lift without surgery
Reduce deep wrinkles
Stimulates collagen production
Helps skin cells renew and repair themselves
Cosmetic-drugs (make-up with SPF
claims, antiperspirant/deodorant)
Presence of drug ingredient, e.g., fluoride
Concentration of ingredient, e.g., AHAs
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New Drug
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Section 201(p): All drugs “new drugs”
except drugs that are:
• GRAS/E = Generally recognized, among
experts qualified by scientific training and
experience to evaluate the safety and
effectiveness of drugs, as safe and effective for
use under the conditions prescribed,
recommended, or suggested in the labeling
and
• Have been used for a material time and to a
material extent
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GRAS/E
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Must be supported by same quantity
and quality of scientific evidence
required to obtain new drug approval
Adequate and well-controlled studies
Published scientific literature
Construed very narrowly by the
courts
19
“Old” Drugs
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FDA has taken the position that it is very
unlikely that any currently marketed
product is an “old” drug (Draft CPG on
Marketed Unapproved Drugs Oct. 2003)
Enforcement Priorities (Draft CPG)
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Drugs with potential safety risks
Drugs that lack evidence of effectiveness
Health fraud drugs
Newly approved drugs (e.g., guaifenesin)
20
Grandfathered Drugs
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Marketed prior to 6/25/38 and no change
in formulation, dosage, strength,
manufacture, indications, etc.
Prior to 10/10/62,
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Used or sold commercially in US
Not a new drug as defined at that time
Not covered by an effective application AND
Composition and labeling have not changed
Construed narrowly by courts
FDA believes that few if any drugs on
market are entitled to grandfather status
21
DESI Review
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Drug Efficacy Study Implementation
National Academy of Sciences-National
Research Council (NAS-NRC)
• Category I (GRAS/E and not misbranded)
• Category II (not GRAS/E)
• Category III (insufficient data)
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If Category I, approved NDA or ANDA still
required
Still ongoing
22
Who Decides?
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No mechanism for administrative
determination of new drug status prior to
marketing
• Old “not new drug” letters revoked (21 CFR
310.100)
• Up to manufacturer to decide whether to
market as “old” drug
• Penalties if FDA determines it is a new drug
marketed without FDA approval
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Manufacturer’s burden to prove
grandfather status (21 CFR
314.200(e)(5))
23
Legal Standard for
New Drug Approval
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Adequate tests of safety under the
conditions prescribed, recommended or
suggested in labeling
Substantial evidence of effectiveness
under the conditions prescribed,
recommended or suggested in labeling
Manufacturing, processing and packing is
inadequate to assure identity, strength,
quality and purity
-- Section 505(d)
24
Adequate Tests of Safety
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Policy:
• Determine the benefit
• Determine the risk
• Weigh the benefit against the risk
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Take into consideration:
• Dosage
• Intended use
• Patient population
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Adequate Tests of Safety
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Procedure:
• Pharmacology studies
• Toxicology studies
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Acute
Subacute
Chronic
Carcinogenicity
Reproductive toxicity
ADME
• Human pharmacokinetics and bioavailability
• Clinical data and adverse events
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Adequate Tests of Safety
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Current issues:
• How to make risky drugs available:
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Patient education
Dispensing though physicians
Evaluating adverse event reports
• Pediatric use
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Opening up access to therapies, while adequately
assuring safety
• Children in clinical trials
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These new issues result in constant
revision of the old standard requiring
“adequate tests”
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Substantial Evidence
of Effectiveness
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“’Substantial evidence’ means evidence consisting of
adequate and well-controlled investigations, including
clinical investigations, by experts qualified by scientific
training and experience to evaluate the effectiveness of the
drug involved, on the basis of which it could fairly and
responsibly be concluded by such experts that the drug will
have the effect it purports or is represented to have under
the conditions of use prescribed, recommended or
suggested in the labeling … thereof.”
“If [FDA] determines, based on relevant science, that data
from one adequate and well-controlled clinical investigation
and confirmatory evidence (obtained prior to or after such
investigation) are sufficient to establish effectiveness,
[FDA] may consider such data and evidence to constitute
substantial evidence for purposes of the preceding
sentence.
-- Section 505(d).
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Substantial Evidence
of Effectiveness
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Adequate and well-controlled studies:
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Clear protocol
Control (e.g., placebo, alternative treatment)
Careful selection of subjects
Procedures to minimize bias (e.g., blinding)
Reliable means of assessing effectiveness
Statistical analysis
-- 21 CFR 314.50, 314.126
29
Substantial Evidence
of Effectiveness
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Adequate and well-controlled
studies:
• Standardized product (identity,
strength, quality, purity, dosage form
• Must be conducted in conformance with:
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IRB regulations
Informed consent regulations
Or, for foreign studies, the Declaration of
Helsinki or more rigorous local requirements
-- 21 CFR 314.50, 314.126
30
Substantial Evidence
of Effectiveness
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Key: Judgment of experts
Senate Report on 1962
Amendments:
• When a drug has been adequately
tested by qualified experts, a claim
should be permitted, even if there is
preponderant evidence to the contrary
• A claim may be made to the medical
profession with a proper explanation of
the basis on which it rests
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Substantial Evidence
of Effectiveness
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“Relative Efficacy” – FDA may not
disapprove a drug on the ground that
a more effective option is available
Often use “intent-to-treat” analysis:
• All randomized patients
• Limited exclusions may be permissible
(“modified intent-to-treat”)
• Defined in advance, based on indication
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Substantial Evidence
of Effectiveness
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Drugs for serious or life-threatening illnesses
FDA must grant “fast track” approval of drug if
• Intended for treatment of serious or life-threatening
illness, and
• Drug demonstrates potential to address unmet needs
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FDA may grant approval based on –
• Surrogate endpoint
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I.e., an endpoint other than survival or irreversible
morbidity that is reasonably likely to predict clinical benefit
Subject to requirement for postmarketing study
• Restrictions, e.g. –
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Specially trained physicians
Performance of specified medical procedures
• Includes special procedures for prompt withdrawal
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-- Section 506 and 21 CFR 314.500 et seq.
Substantial Evidence
of Effectiveness
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Drugs for use in treating serious or lifethreatening conditions caused by exposure to
biological, chemical, radiological or nuclear
substances may be approved based on animal
studies if human exposure would be unethical
Requires:
• Postmarketing studies
• Approval with restrictions
• Information provided to patients
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Includes special procedures for prompt
withdrawal
-- 21 CFR 314.600 et seq.
34
Types of Applications
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Full NDA, or 505(b)(1) NDA
• Data required:
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Chemistry, manufacturing, and controls (CMC) data
Nonclinical pharmacology and toxicology
Human pharmacokinetics and bioavailability
Clinical data
Statistical analysis
Pediatric data
Labeling
Case report forms and tabulations
• May be eligible for exclusivity, and must provide patent
information
• Approval not delayed by patent or exclusivity rights of
other drugs
35
Types of Applications
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505(b)(2) NDA, or “Paper NDA”
• Same as full NDA except –
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The NDA is based on “investigations … relied
on by the applicant for approval of the
application [that] were not conducted by or
for the applicant and for which the applicant
has not obtained a right of reference or use”
Applicant can rely on:
• Published literature
• FDA’s prior safety and effectiveness determination
36
Types of Applications
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505(b)(2) NDA, or “Paper NDA” -- continued
• Same as full NDA except –
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Often used for changes to an approved drug that are not
eligible for approval under an ANDA, e.g.:
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Dosage form
Strength
Route of administration
Change of active ingredient
• May be eligible for exclusivity, and must provide patent
information
• Approval may be delayed by patent or exclusivity rights
of reference listed drug
37
Types of Applications
• Abbreviated New Drug Application
(ANDA), or 505(j) application
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Only for “generic” drugs, i.e., exact or close
copies of already approved drugs
• Identical in active ingredients, dosage form,
strength, route of administration, conditions of
use (some changes in inactive ingredients are
permitted)
• Petition may be submitted for changes in route of
administration, dosage form, and strength, or
substitution of an active ingredient in a
combination product
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Types of Applications
• ANDA – continued
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Data required
• Basis for ANDA (conditions of use, active
ingredients, route of administration)
• CMC data
• Bioequivalence data
• Labeling
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May be eligible for generic exclusivity
Approval may be delayed by patent or
exclusivity rights of reference listed drug
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Biologics and Antibiotics
• Biologics
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Virus, therapeutic serum, toxin, antitoxin, or
analogous product
Regulated under §351 of the Public Health Service
Act and 21 CFR Part 600 et seq.
Biologics License Application (BLA) instead of NDA
CDER: most therapeutic biologics, with certain
exceptions (e.g., cell and gene therapy products and
therapeutic vaccines)
CBER: blood and blood products, vaccines, cell/gene
therapy, certain human tissue for transplantation,
and certain devices for use with blood products
• Antibiotics: regulated as drugs
40