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REGULATORY COURSE

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Title: REGULATORY COURSE


1
REGULATORY COURSE
  • REGULATORY
  • REQUIREMENTS
  • AND
  • STRATEGIES

2
REGULATORY COURSE
3
REGULATORY COURSE
  • Sponsor Activities
  • Preclinical Investigations
  • Identify potential effects of the drug or
    biologic in the body using laboratory and animal
    testing
  • Pharmacology, Toxicology
  • Gather facts on the potential new drug or
    biologic to determine if safe to proceed with
    trials in humans
  • Prior notice of these tests to FDA not required

4
REGULATORY COURSE
  • Preclinical Investigations (Contd)
  • In-vitro and in-vivo testing, and facilities
    used, subject to Good Laboratory Practices
    Regulations (GLPs) 21 CFR 58
  • Unapproved new drugs and biologics can be shipped
    without prior FDA approval or notification if
    properly labeled
  • Need to keep records and available for inspection

5
REGULATORY COURSE
  • Preclinical Investigations (Contd)
  • Testing facility is responsible for the adherence
    to Good Laboratory Practices (GLP) and the these
    regulations create reasons for the involvement of
    the sponsor, to oversee, by virtue of impact on
    the application.

6
REGULATORY COURSE
  • Clinical Investigations
  • Gather facts about the safe and effective use of
    the product in humans to support approval.
  • Requirements for an Investigational New Drug
    Application (IND) detailed under 21 CFR 312

7
REGULATORY COURSE
  • INVESTIGATIONAL NEW DRUG APPLICATION
  • (IND)
  • 21 CFR 312

8
REGULATORY COURSE
  • Investigational New Drug Application
  • Formal notice to the FDA of impending studies
  • Received at least 30 days before start of first
    trial in the U.S.
  • If no objection, IND becomes Effective
  • Trials can start or Agency can initiate a
    Clinical Hold

9
REGULATORY COURSE
  • IND (Contd)
  • Contents of an IND
  • Information on Drug Substance
  • Information on Drug Product
  • Information on proposed clinical program
  • Information on proposed study (Protocol)
  • Principal Investigator (1572)

10
REGULATORY COURSE
  • IND (Contd)
  • Information on the Informed Consent to be signed
    by each subject to ensure that patients enter the
    Trial voluntarily and knowingly (21CFR 50)
  • IRB - local committee that is required by
    regulation 21 CFR 56, to give oversight to the
    clinical investigation to ensure patients are
    adequately protected and that scientific and
    medical standards are met.

11
REGULATORY COURSE
  • IND (Contd)
  • Meetings allowed during IND Phase
  • Pre-IND Meeting
  • Post-IND Submission Meeting
  • End of Phase II Meeting (EOPII)
  • Pre-NDA Meeting

12
REGULATORY COURSE
  • IND (Contd)
  • Phases of Clinical Study
  • Phase I - initial exposure in less than 100
    healthy subjects or patients to evaluate
  • Safety and tolerance, single and multiple rising
    dose, adverse reactions
  • Metabolism - handled in the body
  • Pharmacological - PK/PD

13
REGULATORY COURSE
  • IND (Contd)
  • Phases of Clinical Study
  • Types of acceptable, clinical trials
  • Historical Control
  • Open labeled (No treatment concurrent control)
  • Dose Comparison
  • Placebo Control
  • Active Treatment Control

14
REGULATORY COURSE
  • Phases of Clinical Study (Contd)
  • Phase II - Usually adequate, well-controlled
    trials in small numbers of patients,
    approximately 200 or so. Evaluate efficacy and
    safety of the dose. Sometimes used to define
    optimal dosing.
  • Phase III - Required to be adequate,
    well-controlled trials in larger numbers of
    patients, maybe several thousand, at various
    locations (global). Considered the pivotal
    studies on which to base a determination of safe
    and effective. Approval

15
REGULATORY COURSE
  • NEW DRUG APPLICATION
  • (NDA)
  • 21 CFR 314

16
New Drug Applications (NDA) Requirements
Non-Clinical Pharmacology and Toxicology
Chemistry, Manufacturing and Controls
Safety Information
17
C. T. D.Modules
I
Not part of CTD
Module I
Regional Administrative Information
IIA
Overall Summaries Quality, Nonclinical and
Clinical
Module II
IIC
IIB
Nonclinical Summaries
Clinical Summaries
CTD
IIB1 Written Summaries
IIC1 Written Summaries
IIC2 Tabulated Summaries
IIB2 Tabulated Summaries
V
III
IV
Clinical Data Study Reports
Quality Data Report
Nonclinical Data Study Reports
Raw Data
18
REGULATORY COURSE
  • New Drug Application (NDA)
  • Contents as defined in 21 CFR 314
  • Information on (in great detail)
  • Drug substance, i.e. how to, stability,
    impurities, etc.
  • Drug Product, same as substance, plus
  • Pharmacological and Toxicological findings
  • Clinical Information, and labeling
  • Any and all information known about the drug or
    drug product.

19
REGULATORY COURSE
  • NDA (Contd)
  • Submitted to Center for Drugs Evaluation and
    Review (CDER)
  • Division within Office of New Drugs which is
    responsible for the review of that therapy area
  • Use Form 356H as transmittal form

20
REGULATORY COURSE
  • FDA Activities
  • Actions which can be taken by FDA
  • Refusal to file-
  • NDA is incomplete
  • Improper form ?
  • Omission of critical data
  • Fails to make required certifications

21
REGULATORY COURSE
  • FDA Activities (Contd)
  • Actions to be taken by FDA
  • Review application
  • Drug must be safe effective
  • Risk vs. benefit
  • Substantial evidence
  • evidence from adequate, well-controlled trials
  • usually replicate trials,
  • FDAMA allows for one with confirmatory evidence

22
REGULATORY COURSE
  • FDA Activities (Contd)
  • Safe and effective
  • Need adequate tests to showdrug is safe
    effective for use, under conditions prescribed in
    labeling
  • Benefit vs Risk
  • FDA evaluates drugs effective against risks
    associated with use of drug determine if benefit
    outweighs risks (seriousness of disease, unmet
    medical need, etc.)

23
REGULATORY COURSE
  • FDA Activities (Contd)
  • Adequacy of manufacturing and controls
  • Pre-approval Inspection (PAI) - compliance with
    cGMP
  • Labeling review, usually last step.
  • Advisory Committee - Optional, but usually for
    NCEs. FDAMA requires decision within 90 days.

24
REGULATORY COURSE
  • FDA Activities (Contd)
  • Discipline review letters
  • Action Letters
  • Non-approval - major issues of safety or efficacy
  • Approvable - addressable deficiencies
  • Approval - all issues resolved

25
REGULATORY COURSE
  • FDA Activities (Contd)
  • Timeframes
  • Prescription Drug User Fee Act (PDUFA)
  • More reviewers to meet demand of submissions
  • Established timelines
  • Priority Review - 6 months
  • Standard Review - 10 months
  • Faster review times

26
REGULATORY COURSE
  • FDA Activities (Contd)
  • Other Reviews
  • Fast Track
  • Joint program with FDA, quick, rolling review and
    approval
  • Accelerated Approval
  • Approval granted for limited indication until
    additional Clinical trials are completed. If
    unsuccessful, the product is quickly withdrawn.
    Other restrictions enforced.

27
REGULATORY COURSE
  • Market Exclusivity
  • Five Year Exclusivity
  • Available only to drug products with new chemical
    entities. Excludes esterified forms, salts,
    chelates, complexes or clathrates of the
    molecule.
  • Example a compound, other than an ester, that
    requires metabolic conversion to produce an
    already approved active moiety is considered a
    new chemical entity and entitled to 5 yrs.
    exclusivity

28
REGULATORY COURSE
  • Market Exclusivity
  • Three Year Exclusivity
  • Available to drug products for which the
    application or supplement contains new clinical
    investigations conducted by the sponsor deemed
    essential for approval.

29
REGULATORY COURSE
  • NDA Postapproval Requirements
  • Annual Reports
  • Manufacturing Info
  • Stability Info
  • Production Info
  • Study Info
  • Safety Reports
  • Alert reports
  • Periodic Reports

30
REGULATORY COURSE
  • BIOLOGICALS
  • AND THE
  • BIOLOGICS LICENSE
  • APPLICATION
  • (BLA)

31
REGULATORY COURSE
  • HISTORICAL BACKGROUND
  • Smallpox Vaccine - Variolation
  • Counterfeit products
  • Tetanus outbreaks for smallpox and diphtheria
    vaccines
  • Biologics Act of 1902, reenacted in 1944 as part
    of the Public Health Services Act, USC 351

32
REGULATORY COURSE
  • HISTORICAL BACKGROUND (Contd)
  • FDAs oversight of Biologicals via Bureau of
    Biologics until 1982.
  • Bureau of Drugs and Biologics until 1988
  • Center for Biologics Evaluation and Research

33
REGULATORY COURSE
  • DEFINITION(21 CFR 600.3)
  • means any virus, therapeutic serum, toxin,
    antitoxin, or analogous product applicable to the
    prevention, treatment or cure of diseases or
    injuries in man.

34
REGULATORY COURSE
  • DEFINITION (PHS Act)
  • any virus, therapeutic serum, toxin, antitoxin,
    vaccine, blood, blood component or derivative,
    allergenic product, or analogous product, or
    arsphenamine or its derivatives (or any other
    trivalent organic arsenic compound), applicable
    to the prevention, treatment, or cure of
    diseases, or injuries in man

35
REGULATORY COURSE
  • CBER Oversight Of Biologics
  • Development and Investigation of Biologicals
  • 21 CFR 312
  • Biologics License Applications
  • 21 CFR 600

36
REGULATORY COURSE
  • Comparison of Biologics and Drugs
  • Products are plant specific
  • Prior to BLA, required two separate applications
  • Product License Application
  • Establishment License Application
  • Biologicals are more difficult to characterize
    and identify
  • May require clinical testing to confirm sameness

37
REGULATORY COURSE
  • Comparison of Biologics and Drugs
  • Intercenter Agreements
  • Vaccines
  • in vivo diagnostic allergenic extracts and
    allergens for hyposensitization
  • immunoglobulin products
  • proteins made in the body
  • animal venom

38
REGULATORY COURSE
  • Comparison of Biologics and Drugs
  • Stages of Development
  • IND - Same as for drugs
  • Preclinical - watch for immune responses
  • Clinical - watch for antibody activity
    (neutralizing)
  • Submission - BLA vs. NDA
  • Review - Prior to PDUFA, no timelines
  • Post approval requirements - Same as for Drugs

39
REGULATORY COURSE
  • BIOLOGICALSVS.
  • BIOTECHNOLOGY

40
REGULATORY COURSE
  • BIOLOGICALS -
  • Agents or products as defined in the law and the
    regulations
  • BIOTECHNOLOGY -
  • A Process!!!!

41
REGULATORY COURSE
  • LABELING

42
REGULATORY COURSE
  • Labeling 21 CFR 201
  • Very Important part of the NDA
  • Format and Content
  • General requirements.
  • 21 CFR 201.56
  • Specific requirements.
  • 21 CFR 201.57

43
REGULATORY COURSE
  • Labeling (Contd)
  • Format and Content
  • Description
  • Names
  • Therapy class
  • Clinical Pharmacology
  • Indications and Usage
  • Used as basis of review

44
REGULATORY COURSE
  • Labeling (Contd)
  • Format and Content
  • Contraindications
  • hypersensitivity, age, sex, concom meds.
  • Warnings
  • Serious AEs, potential safety hazards
  • Precautions
  • Special Care for safe use, i.e. labs,
    carcinogenesis, pregnancy, etc.

45
REGULATORY COURSE
  • Labeling (Contd)
  • Format and Content
  • Common adverse reactions
  • Drug abuse and dependence
  • Overdose
  • Dosage administration
  • How supplied
  • Animal pharmacology (optional)

46
REGULATORY COURSE
  • ABBREVIATED NEW
  • DRUG APPLICATIONS
  • (ANDA)
  • (GENERIC DRUGS)

47
New Drug Applications (NDA) Requirements
Non-Clinical Pharmacology and Toxicology
Chemistry, Manufacturing and Controls
Safety Information
48
Abbreviated New Drug Applications - Core Contents
-
Patent Certifications
Chemistry, Manufacturing, Controls
49
REGULATORY COURSE
  • CMC BULK ACTIVE
  • Typically, bulk active is obtained from a
    supplier.
  • ANDA applicant references suppliers DMF.
  • Specifications and analytical methods for the
    active can be found in USP, BP, EP if compendial
  • For non-compendial items, supplier can
    recommend/provide methods to applicant
  • No bulk stability data required in ANDA

50
REGULATORY COURSE
  • CMC FINISHED PRODUCT
  • Similar requirements to NDA (21 CFR
    314.50(d)(1)),
  • Example
  • - Components/composition
  • - Specifications and analytical methods
  • - in-process controls
  • - executed batch records

51
REGULATORY COURSE
  • CMC FINISHED PRODUCT (continued)
  • One pilot batch of each strength submitted
  • Batch scale considerations
  • - 10x scaling rule in effect
  • Blank, scaled-up batch records required for
  • proposed commercial batches
  • 3 mos accelerated stability required

52
REGULATORY COURSE
Office of Generics requires comparative synopsis
of generic and reference drug with respect
to conditions of use, active ingredient(s),
route of administration dosage form and
strength(s).
53
REGULATORY COURSE
  • Bioequivalence
  • ANDA applicant required to demonstrate
    Bioequivalence of generic drug with the
    reference or listed drug.
  • FDAs Approved Drug Products with Therapeutic
    Equivalence Evaluations (Orange Book) source
    for listed drug and strengths

54
REGULATORY COURSE
  • Orange Book Bioequivalence Ratings
  • Drug Codes beginning with A considered
    therapeutically equivalent example AB rating
    designates therapeutically equivalent to
    innovator or listed drug
  • Drug Codes beginning with B considered NOT
    therapeutically equivalent example BC rating
    denotes bioavailability differences between
    extended-release dosage forms (generic vs.
    listed)

55
REGULATORY COURSE
  • Codes Considered Therapeutically Equivalent
  • AA Products in conventional dosage forms not
  • presenting problems.
  • AB Products meeting necessary BE requirements.
  • AN Solutions or powders intended for
    aerosolization.
  • AO Injectable oil solutions.
  • AP Injectable aqueous solutions.
  • AT Topical Products.

56
REGULATORY COURSE
  • Codes Considered NOT Therapeutically Equivalent
  • BC Extended release dosage forms with
    bioavailability differences
  • BD Active ingredients and dosage forms with
    documented BE problems.
  • BE Delayed release oral dosage forms.
  • BN Products in aerosol-nebulizer systems
    (compatible with specific delivery system).

57
REGULATORY COURSE
  • Codes Considered NOT Therapeutically Equivalent
    (Contd)
  • BP Active ingredients and dosage forms with
    potential BE problems
  • BR Suppositories or enemas that deliver drugs
    for systemic absorption.
  • BS Products having drug standard deficiencies
    (standard for active ingredient inadequate for
    FDA evaluation).
  • BT Topical products with BE issues.

58
REGULATORY COURSE
  • Bioequivalence
  • Comparison of AUC, CMAX and TMAX (85 - 115)
  • Bioequivalence testing varies between dosage
    forms
  • IR Solid Oral (single dose/fasting)
  • Extended Release (fed/fasted single fasted
    multiple dose)
  • Creams, Ointments (clinical endpoints)
  • Solutions, Injectables, Inhalation products
    (bio waiver)

59
REGULATORY COURSE
  • Bioequivalence
  • Criteria for waiver of evidence of in vivo
    bioavailability or bioequivalence (21 CFR
    320.22)
  • Parenteral Solution
  • Same active and inactive ingredients in the same
    concentration as innovator drug.
  • Inhalation Solution
  • Same active ingredient as innovator drug.

60
REGULATORY COURSE
  • Bioequivalence
  • Solution (skin, oral solution, elixir, syrup,
    tincture, or similar other solubilized form
  • Same active drug ingredient in the same
    concentration and dosage form as innovator drug
    and contains no inactive ingredient or other
    change in formulation from the innovator drug.

61
REGULATORY COURSE
  • Bioequivalence
  • Tablets (excluding Controlled Release or
    Extended Release) Same dosage form, but different
    strength, and is proportionally similar in its
    active inactive ingredients to another drug
    product for which the same manufacturer has
    obtained approval and the following conditions
    are met
  • (i) The bioavailability of this other drug
    product has been demonstrated
  • (ii) Both products meet an appropriate in vitro
    test
  • OR
  • In vitro/In vivo Correlation
    established.

62
REGULATORY COURSE
  • Generic Labeling
  • ANDA applicant required to copy innovator
    labeling
  • and substitute unique identifiers (i.e. removal
    of
  • trade name, NDC numbers, How Supplied Sections)
  • Package insert requires an annotated side-by-side
  • comparison between proposed generic and
    innovator
  • insert.

63
REGULATORY COURSE
  • INVESTIGATIONAL NEW DRUGS
  • REGULATIONS
  • TREATMENT USE AND SALE

64
REGULATORY COURSE
  • Use of Investigational New Drugs for Treatment
  • Treatment IND
  • Established by regulation in 1987, codified by
    FDAMA, allows an investigational drug to be made
    available to patients, outside of controlled
    trials, for serious, life-threatening diseases
    for which there is no comparable or satisfactory
    alternative therapy available.

65
REGULATORY COURSE
  • Use of Investigational New Drugs for Treatment
  • Conditions
  • Drug is intended for such use
  • There is no alternative available
  • Drug is under investigation in controlled trials
    or trials are completed
  • Sponsor is actively pursuing market approval

66
REGULATORY COURSE
  • Use of Investigational New Drugs for Treatment
    (Contd)
  • Amended, after considerable comment to
  • May be effective for intended use in intended
    population
  • Would not expose intended patients to an
    unreasonable and additional significant risk
  • In all cases, Sponsor may not commercialize an
    Investigational Drug by charging a price higher
    than required to recover RD, manufacturing and
    handling costs

67
REGULATORY COURSE
  • Use of Investigational New Drugs for Treatment
    (Contd)
  • FDA continues to sanction Compassionate, Open
    Label and Parallel Track INDs.
  • All three similar, with Parallel Track used in
    earlier phases
  • Group C Drugs
  • Obtained by physician from NCI
  • Promising new Investigational Drugs
  • Treated as Treatment INDs by FDA

68
REGULATORY COURSE
  • EXPEDITED DEVELOPMENT
  • AND
  • REVIEW INIATIVES

69
REGULATORY COURSE
  • 4 MAJOR INITIATIVES
  • Subpart E
  • Accelerated Approval (Subpart H)
  • Priority Review
  • Fast Track
  • Fast Track Program
  • Fast Track Product
  • Different schemes
  • Dont use terms interchangeably

70
REGULATORY COURSE
71
REGULATORY COURSE
  • The Secretary shall facilitate the development
    and expedite the review of a drug if it is
    intended for the treatment of a serious or life
    threatening condition and it demonstrates the
    potential to address unmet medical needs for such
    a condition.

72
REGULATORY COURSE
  • Components (4 parts)
  • 506(a) Designation of a Drug for Fast Track,
    request by Sponsor
  • 506(b) Approval of Application
  • Based on clinical endpoints or surrogate
    endpoints
  • Limitations
  • 506(c) Review of Incomplete Applications, Rolling
    NDA
  • 506(d) Awareness Efforts,

73
REGULATORY COURSE
  • FAST TRACK PROGRAM, FIRST QUESTIONS
  • Are you eligible for fast track designation?
  • Guidance for Industry Fast Track Drug
    Development Programs - Designation, Development
    and Application Review Sept 1998
  • Are you eligible for other regulatory options
    accelerated approval, priority review, Subpart E
    approval

74
FAST TRACK ALGORITHM
Is some aspect of the condition serious or
life-threatening?
No
Not FT
Yes possibly FT
Does the drug show potential to treat a serious
aspect of the condition?
No
Not FT
Yes, possible FT
Is the drug development program designed to
determine whether the drug will effect a serious
aspect of the condition?
No Not FT
Yes, possible FT
75
FAST TRACK ALGORITHM
Is there any approved treatment for the serious
or life-threatening aspect of the condition being
studied?
FT
No
Yes, possibly FT
Is a medical need unmet by available treatments
No
Not FT
Yes, possibly FT
Is that unmet medical need being studied with
this product?
No
Not FT
Yes
FT
76
REGULATORY COURSE
  • FAST TRACK CONDITIONS
  • Multiple meetings (pre-IND through labeling
    discussions)
  • Possible Accelerated Approval (surrogate
    endpoint)
  • Possible approval under Subpart E (less safety
    data than normal)
  • Priority review designation
  • Portion of an application eligible for early
    submission

77
REGULATORY COURSE
  • ROLLING REVIEW
  • Caveats
  • Review complete portions of an NDA
  • Filing awaits complete application
  • Scheduling of review TBD by division
  • User fee must be paid with first portion
  • Review clock starts with complete NDA

78
REGULATORY COURSE
  • ROLLING REVIEW (Contd)
  • Eligibility for Priority Review and Accelerated
    Approval (unlinked)
  • Efficacy standard in 505(d) (unlinked)

79
REGULATORY COURSE
  • SUMMARY
  • To Qualify
  • Intended to treat a serious disease
  • Has the potential to address an unmet medical
    need
  • Development plan evaluates that potential
  • Guidance is comprehensive resource

80
REGULATORY COURSE
  • ORPHAN DRUGS

81
REGULATORY COURSE
  • Requirements for NDA Approval Are Difficult
  • Rare Diseases
  • Low Use
  • Potential Sales Do Not Justify Research Costs
  • Use Orphan IND to Treat Patients
  • Contrary to Statute - 505 (i)
  • HHS Report - Significant Drugs of Limited
    Commercial Potential (6/79)

82
REGULATORY COURSE
  • Orphan Drug Act (1983)
  • Two Incentives
  • Amended Internal Revenue Code to provide Tax
    Benefits for Clinical Research
  • Provide Sponsors with Written Requirements for
    Human and Animal Studies
  • Provide Seven Years Exclusivity for First Approval

83
REGULATORY COURSE
  • Definition of Rare Disease
  • Less than 200,000 cases in US
  • Less than 10,000 new cases per year
  • Applies to Patented and Not Patented Drugs
  • Can Apply for Orphan Drug Status at Any Time
    During Research and Development Process
  • Must Be Assigned Orphan Drug Status Prior to
    Approval

84
REGULATORY COURSE
  • Over - the - Counter Drugs
  • (OTC)

85
REGULATORY COURSE
  • OTC Drugs
  • Food Drug and Cosmetic Act, 1938
  • Clear distinction between prescription and OTC
    drugs
  • Many requirements applied to both classes
  • Amendments, 1962
  • Mandate to review all previously approved NDAs,
    applied to OTC drugs as well
  • Many OTC drugs not considered covered by NDAs

86
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Estimated from 100,000 to one-half million
    products on market
  • Very few approved through new drug procedures as
    set out in section 505 of act.
  • Some excluded from new drug definition by the
    1938 Act and 1962 Amendments by the grandfather
    clause (201(p)(1) and 107(c) respectively
  • Labeling requirements still remain

87
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Three ways to switch a drug from RX to OTC
  • Sponsor of NDA or ANDA submits a supplemental
    application requesting FDA to approve the switch
  • The manufacturer, or in theory any person, can
    submit a petition to FDA under 21 CFR 310.200. If
    switched, it is listed in 310.201.
  • Through review procedure established under 21 CFR
    330 or amendment to an established drug monograph

88
REGULATORY COURSE
  • OTC Drugs (Contd)
  • FDA wanted all unapproved or misbranded drugs -
    reformulated or relabeled to meet requirements
  • If not, remove it from the market
  • Methods for accomplishing tasks
  • Initiate separate court actions for each
    violative OTC
  • Deal with OTC products through rule making by
    therapeutic class, on an industry wide basis

89
REGULATORY COURSE
  • OTC Drugs (Contd)
  • FDA chose the rule making approach because
  • Limited resources, overwhelmed by review of
    safety efficacy for each OTC product
  • Litigation would be massive in time expense
  • Litigation could not be done simultaneously
  • There would probably be 1938 1962 grandfather
    clause drugs that would escape action
  • Paramount concern is inadequate consumer
    protection
  • Almost all OTC drugs on market come from 200
    actives

90
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Accordingly, the Commissioner proposes to
    establish procedures for rule making which will
    result in classifying some OTC products as
    generally regarded as safe and effective and not
    misbranded under prescribed, recommended, or
    suggested conditions of use
  • Any OTC drug that is not, will require an NDA
    prior to marketing

91
REGULATORY COURSE
  • OTC Drugs (Contd)
  • In 1972, FDA proposed an expert advisory
    committee review
  • The NAS-NRC review covered 420 OTC drugs
  • Broadly representative of entire OTC market
  • Commonly referred to as The Monograph Reviews
  • FDA established the procedure in 21 CFR 330

92
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Procedures for classifying OTC drugs at GRASE -
    21 CFR 330
  • Advisory Committee Panels -
  • Qualified experts appointed by the Commissioner
  • Review OTC drug labeling
  • promulgate monographs establishing conditions
    under which OTC drugs are GRASE, and not
    misbranded
  • Panel members chosen from lists submitted by
    professional, consumer and industry interested
    parties

93
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Procedures for classifying OTC drugs at GRASE -
    21 CFR 330
  • Deliberations of the panel
  • Review all data submitted to it
  • Prepare a report with conclusions on GRASE
    ingredients for each category of OTC drugs
  • Any person can request time to present views, can
    be denied
  • Any person can present written data and views for
    review
  • The panel shall apply the following standards

94
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Procedures for classifying OTC drugs at GRASE -
    21 CFR 330
  • Standards for Safety
  • Safety means a low incidence of ARs or
    Significant side effects, under adequate
    direction for use, as well as low potential for
    harm
  • Proof of safety shall consist of adequate tests,
    material extent
  • Proof shall include results of significant human
    experience, material time
  • General recognition based on published studies
    supported by unpublished studies.

95
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Procedures for classifying OTC drugs at GRASE -
    21 CFR 330
  • Standards for Effectiveness
  • Reasonable expectation of desired pharmacological
    effect when used as directed
  • Proof consists of controlled clinical trials as
    per 314.111(a)(5)(ii)
  • Proof can be supported by uncontrolled studies
  • Significant human marketing experience
  • GRAE based on published and unpublished data

96
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Procedures for classifying OTC drugs at GRASE -
    21 CFR 330
  • Standards for Effectiveness
  • Benefit to risk ratio is considered in
    determining S E
  • May combine two or more GRASE ingredients
  • Apply combo regulations

97
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Procedures for classifying OTC drugs at GRASE -
    21 CFR 330
  • Report to the Commissioner
  • Recommend monograph(s) covering the category of
    OTC drugs establishing conditions for GRASE
    (Category I)
  • A statement of all actives, labeling claims, or
    other statements or other conditions reviewed and
    excluded because not GRASE (Category II)
  • A statement of all actives, labeling claims, or
    other statements or other conditions reviewed and
    excluded because not sufficient data to determine
    GRASE (Category III)

98
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Procedures for classifying OTC drugs at GRASE -
    21 CFR 330
  • Actions to the Commissioner
  • Proposed Monograph - After review, publish in the
    FR
  • A monograph(s) establishing conditions for GRASE
  • Statement of Conditions excluded based on not
    being GRASE
  • Statement of conditions excluded based on
    insufficient data
  • Full reports of panel to Commissioner
  • Comment period established

99
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Procedures for classifying OTC drugs at GRASE -
    21 CFR 330
  • Actions to the Commissioner
  • Tentative Final Monograph
  • After review of all comments and replies, on
    Proposed Monograph, Commissioner publishes a
    tentative order
  • TFM establishes the conditions under which a
    category of OTC drugs will be recognized as
    GRASE
  • Interested parties have 30 days to respond,
    submit written comments, objections or suggestions

100
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Procedures for classifying OTC drugs at GRASE -
    21 CFR 330
  • Actions to the Commissioner
  • Tentative Final Monograph (contd)
  • Any party can request an oral hearing on
    objections to TFM
  • If grounds are reasonable for oral hearing,
    Commissioner can schedule

101
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Procedures for classifying OTC drugs at GRASE -
    21 CFR 330
  • Actions to the Commissioner
  • After reviewing all comments and objections that
    have been filed the Commissioner shall publish a
    Final Monograph a final order containing a
    monograph which establishes the conditions under
    which a category of OTC drugs can be generally
    recognized as GRASE and not misbranded.
  • Only a court can overturn
  • Regulatory action for all products that do not
    conform

102
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Procedures for classifying OTC drugs at GRASE -
    21 CFR 330
  • Legality of OTC drug review ?
  • Never challenged
  • FDA request for data
  • No power to request,
  • favorable vs. unfavorable data
  • Combination OTC drugs
  • Encouraged reformulation

103
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Procedures for classifying OTC drugs at GRASE -
    21 CFR 330
  • Homeopathic drugs deferred - not GRAE
  • NDAs withdrawn when final monograph issued
  • Enforcement policy - case by case
  • Daytime Sedatives - withdrawn
  • Premature marketing - Rush to Market based on
    panel discussions.

104
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Cases for Discussion
  • Benylin Case p417
  • Ibuprofen Case p417
  • Metaproterenol p418

105
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Procedures for classifying OTC drugs at GRASE -
    21 CFR 330
  • New Combinations not in the monograph, not
    allowed
  • Deviations required NDAs, but only for the
    deviation
  • Professional labeling allowed
  • Prescription vs. OTC indication
  • Reopening the Monograph process has been resisted

106
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Procedures for classifying OTC drugs at GRASE -
    21 CFR 330
  • The Legality of Category III
  • Cutler vs. Kennedy (p605)

107
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Procedures for classifying OTC drugs at GRASE -
    21 CFR 330
  • The Legality of Category III
  • Cutler vs. Kennedy (p605)
  • Category III flies in the face of the FDC Act
  • Essentially left to the discretion of the Agency
  • FDA established final position 9/29/81, 46FR47739
  • Followed Court, deleted Category III when FM
    published

108
REGULATORY COURSE
  • OTC Drugs (Contd)
  • Regulation of Advertising
  • FDA - Prescription product ads and promotion
  • FTC - OTC drugs
  • Two agencies are supposed to cooperate with each
    other
  • Only claims in the final monograph(s) are allowed
  • Monograph drugs
  • NDA OTC drugs

109
REGULATORY COURSE
  • OTC Drugs (Contd)
  • 21 CFR 200 Subpart C
  • Labeling requirements for Over-the-Counter Drug
    Products
  • 201.60 Principal Display Carton
  • 201.61 Statement of identity
  • 201.62 Declaration of net quantity of contents
  • 201.63 Pregnancy/breast-feeding warning
  • 201.64 Sodium labeling
  • 201.66 Format and content requirements for OTC
    drug product labeling

110
REGULATORY COURSE
  • DEVICES

111
REGULATORY COURSE
  • DEFINITION
  • a) ..an instrument, apparatus, implement,
    machine, .
  • b) recognized in official compendia
  • c) must not achieve desired effect through
    chemical action within the body, or require
    metabolization to achieve its intended purpose

112
REGULATORY COURSE
  • CLASSIFICATION OF DEVICES
  • Class I - devices for which neither a standard
    nor pre-market approval are warranted because
    general regulatory controls available under the
    FDC Act are sufficient to assure safety and
    efficacy

113
REGULATORY COURSE
  • CLASSIFICATION OF DEVICES
  • Class II - includes those devices for which
    general controls that exist under the FDC Act
    are not sufficient to assure safety and efficacy,
    and for which enough information exists to
    develop a performance standard.

114
REGULATORY COURSE
  • CLASSIFICATION OF DEVICES
  • Class III - includes those devices for which
    general controls are not sufficient to assure
    safety and effectiveness, and there is not
    sufficient information to establish a performance
    standard.

115
REGULATORY COURSE
  • Introduction of a new device
  • Since 1976 Amendments - only three ways-
  • 1) substantially equivalent to a pre-enactment
    device for which a PMN (Pre-market Notification)
    had been submitted to FDA under section 510(k)
  • 2) under a PMA (Pre-Market Approval) application,
    submitted and approved by FDA
  • 3) as a device that has been reclassified by FDA
    from Class III to Class I or II.

116
REGULATORY COURSE
  • THE END
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