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REGULATORY COURSE. REGULATORY REQUIREMENTS AND STRATEGIES. REGULATORY COURSE. REGULATORY COURSE. Sponsor Activities: Preclinical Investigations: Identify potential effects of the drug or biologic in the body using laboratory and animal testing Pharmacology, Toxicology

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REGULATORY COURSE

REGULATORY

REQUIREMENTS

AND

STRATEGIES



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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


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  • Preclinical Investigations (Cont’d):

    • 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


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REGULATORY COURSE

  • Preclinical Investigations (Cont’d)

    • 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.


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  • 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


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INVESTIGATIONAL NEW DRUG APPLICATION

(IND)

21 CFR 312


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  • 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”


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  • IND (Cont’d)

    • 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)


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  • IND (Cont’d)

    • 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.


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  • IND (Cont’d)

    • Meetings allowed during IND Phase:

      • Pre-IND Meeting

      • Post-IND Submission Meeting

      • End of Phase II Meeting (EOPII)

      • Pre-NDA Meeting


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  • IND (Cont’d)

    • 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


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  • IND (Cont’d)

    • Phases of Clinical Study

      • Types of acceptable, clinical trials:

        • Historical Control

        • Open labeled (No treatment concurrent control)

        • Dose Comparison

        • Placebo Control

        • Active Treatment Control


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  • Phases of Clinical Study (Cont’d)

    • 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”


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NEW DRUG APPLICATION

(NDA)

21 CFR 314


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NDA Summary Section

Labeling

Patent Information

Pharmacokinetics and

Bioavailability

Statistical Section

Clinical Data Section

New Drug Applications (NDA) Requirements

Non-Clinical Pharmacology

and Toxicology

Chemistry, Manufacturing

and Controls

Safety Information


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C. T. D.Modules

I

Not part of CTD

Module I

Regional Administrative Information

IIA

Overall Summaries

Quality, Nonclinical and Clinical

Module II

IIB

IIC

Nonclinical Summaries

Clinical Summaries

CTD

IIC1 Written Summaries

IIC2 Tabulated Summaries

IIB1 Written Summaries

IIB2 Tabulated Summaries

V

III

IV

Quality Data Report

Nonclinical Data Study Reports

Clinical Data Study Reports

Raw Data


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  • 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.


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  • NDA (Cont’d)

    • 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


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  • 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


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  • FDA Activities (Cont’d)

    • 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


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  • FDA Activities (Cont’d)

    • Safe and effective:

      • Need adequate tests to showdrug is safe & effective for use, under conditions prescribed in labeling

    • Benefit vs Risk

      • FDA evaluates drug’s effective against risks associated with use of drug determine if benefit outweighs risks (seriousness of disease, unmet medical need, etc.)


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  • FDA Activities (Cont’d)

    • 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.


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  • FDA Activities (Cont’d)

    • Discipline review letters:

    • Action Letters:

      • Non-approval - major issues of safety or efficacy

      • Approvable - addressable deficiencies

      • Approval - all issues resolved


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  • FDA Activities (Cont’d)

    • 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


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  • FDA Activities (Cont’d)

    • 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.


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  • 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


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  • 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.


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  • NDA Postapproval Requirements

    • Annual Reports

      • Manufacturing Info

      • Stability Info

      • Production Info

      • Study Info

    • Safety Reports

      • Alert reports

      • Periodic Reports


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BIOLOGICALS

AND THE

BIOLOGICS LICENSE

APPLICATION

(BLA)


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  • 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


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  • HISTORICAL BACKGROUND (Cont’d):

    • FDA’s oversight of Biologicals via Bureau of Biologics until 1982.

    • Bureau of Drugs and Biologics until 1988

    • Center for Biologics Evaluation and Research


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  • 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.”


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  • 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…”


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  • CBER Oversight Of Biologics:

    • Development and Investigation of Biologicals:

      • 21 CFR 312

    • Biologics License Applications

      • 21 CFR 600


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  • 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


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  • 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


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  • 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


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BIOLOGICALSVS.

BIOTECHNOLOGY


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  • BIOLOGICALS -

    • Agents or products as defined in the law and the regulations

  • BIOTECHNOLOGY -

    • A Process!!!!



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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


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Labeling (Cont’d)

Format and Content

Description:

Names

Therapy class

Clinical Pharmacology

Indications and Usage

Used as basis of review


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Labeling (Cont’d)

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.


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REGULATORY COURSE

Labeling (Cont’d)

Format and Content

Common adverse reactions

Drug abuse and dependence

Overdose

Dosage & administration

How supplied

Animal pharmacology (optional)


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REGULATORY COURSE

ABBREVIATED NEW

DRUG APPLICATIONS

(ANDA)

(GENERIC DRUGS)


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NDA Summary Section

Labeling

Patent Information

Pharmacokinetics and

Bioavailability

Statistical Section

Clinical Data Section

New Drug Applications (NDA) Requirements

Non-Clinical Pharmacology

and Toxicology

Chemistry, Manufacturing

and Controls

Safety Information


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Bioequivalence Data/Waiver

Labeling

Abbreviated New Drug Applications - Core Contents -

Patent Certifications

Chemistry, Manufacturing, Controls


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  • CMC: BULK ACTIVE

  • Typically, bulk active is obtained from a supplier.

  • ANDA applicant references supplier’s 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


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  • 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


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  • 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


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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).


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  • Bioequivalence

    • ANDA applicant required to demonstrate Bioequivalence of generic drug with the reference or “listed” drug.

    • FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (“Orange Book”) source for listed drug and strengths


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  • 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)


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  • 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.


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  • 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).


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  • Codes Considered NOT Therapeutically Equivalent: (Cont’d)

    • 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.


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  • 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)


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  • 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.


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  • 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.


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  • 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.


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  • 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.


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REGULATORY COURSE

INVESTIGATIONAL NEW DRUGS

REGULATIONS:

TREATMENT USE AND SALE


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  • 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.


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  • 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


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  • Use of Investigational New Drugs for Treatment: (Cont’d)

    • 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 R&D, manufacturing and handling costs


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  • Use of Investigational New Drugs for Treatment: (Cont’d)

    • 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


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EXPEDITED DEVELOPMENT

AND

REVIEW INIATIVES


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  • 4 MAJOR INITIATIVES

    • Subpart E

    • Accelerated Approval (Subpart H)

    • Priority Review

    • Fast Track

      • Fast Track Program

      • Fast Track Product

    • Different schemes

    • Don’t use terms interchangeably



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  • 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 conditionandit demonstrates the potential to address unmet medical needs for such a condition.


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  • 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,


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  • 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


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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


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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


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  • 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


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  • 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


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  • ROLLING REVIEW (Cont’d)

    • Eligibility for Priority Review and Accelerated Approval (unlinked)

    • Efficacy standard in 505(d) (unlinked)


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  • 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


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ORPHAN DRUGS


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  • 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)


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  • 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


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  • 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


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Over - the - Counter Drugs

(OTC)


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  • 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


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  • OTC Drugs (Cont’d)

    • 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


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  • OTC Drugs (Cont’d)

    • 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


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  • OTC Drugs (Cont’d)

    • 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


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  • OTC Drugs (Cont’d)

    • 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


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  • OTC Drugs (Cont’d)

    • 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


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  • OTC Drugs (Cont’d)

    • 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


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  • OTC Drugs (Cont’d)

    • Procedures for classifying OTC drugs at GRAS&E - 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 GRAS&E, and not misbranded

        • Panel members chosen from lists submitted by professional, consumer and industry interested parties


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  • OTC Drugs (Cont’d)

    • Procedures for classifying OTC drugs at GRAS&E - 21 CFR 330

      • Deliberations of the panel

        • Review all data submitted to it

        • Prepare a report with conclusions on GRAS&E 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


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REGULATORY COURSE

  • OTC Drugs (Cont’d)

    • Procedures for classifying OTC drugs at GRAS&E - 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.


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REGULATORY COURSE

  • OTC Drugs (Cont’d)

    • Procedures for classifying OTC drugs at GRAS&E - 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


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REGULATORY COURSE

  • OTC Drugs (Cont’d)

    • Procedures for classifying OTC drugs at GRAS&E - 21 CFR 330

      • Standards for Effectiveness

        • Benefit to risk ratio is considered in determining S & E

        • May combine two or more GRAS&E ingredients

          • Apply combo regulations


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REGULATORY COURSE

  • OTC Drugs (Cont’d)

    • Procedures for classifying OTC drugs at GRAS&E - 21 CFR 330

      • Report to the Commissioner

        • Recommend monograph(s) covering the category of OTC drugs establishing conditions for GRAS&E (Category I)

        • A statement of all actives, labeling claims, or other statements or other conditions reviewed and excluded because not GRAS&E (Category II)

        • A statement of all actives, labeling claims, or other statements or other conditions reviewed and excluded because not sufficient data to determine GRAS&E (Category III)


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REGULATORY COURSE

  • OTC Drugs (Cont’d)

    • Procedures for classifying OTC drugs at GRAS&E - 21 CFR 330

      • Actions to the Commissioner

        • Proposed Monograph - After review, publish in the FR

          • A monograph(s) establishing conditions for GRAS&E

          • Statement of Conditions excluded based on not being GRAS&E

          • Statement of conditions excluded based on insufficient data

          • Full reports of panel to Commissioner

        • Comment period established


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REGULATORY COURSE

  • OTC Drugs (Cont’d)

    • Procedures for classifying OTC drugs at GRAS&E - 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 GRAS&E

          • Interested parties have 30 days to respond, submit written comments, objections or suggestions


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REGULATORY COURSE

  • OTC Drugs (Cont’d)

    • Procedures for classifying OTC drugs at GRAS&E - 21 CFR 330

      • Actions to the Commissioner

        • Tentative Final Monograph (cont’d)

          • Any party can request an oral hearing on objections to TFM

          • If grounds are reasonable for oral hearing, Commissioner can schedule


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REGULATORY COURSE

  • OTC Drugs (Cont’d)

    • Procedures for classifying OTC drugs at GRAS&E - 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 GRAS&E and not misbranded.

      • Only a court can overturn

      • Regulatory action for all products that do not conform


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REGULATORY COURSE

  • OTC Drugs (Cont’d)

    • Procedures for classifying OTC drugs at GRAS&E - 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


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REGULATORY COURSE

  • OTC Drugs (Cont’d)

    • Procedures for classifying OTC drugs at GRAS&E - 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.


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REGULATORY COURSE

  • OTC Drugs (Cont’d)

    • Cases for Discussion

      • Benylin Case p417

      • Ibuprofen Case p417

      • Metaproterenol p418


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REGULATORY COURSE

  • OTC Drugs (Cont’d)

    • Procedures for classifying OTC drugs at GRAS&E - 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


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REGULATORY COURSE

  • OTC Drugs (Cont’d)

    • Procedures for classifying OTC drugs at GRAS&E - 21 CFR 330

      • The Legality of Category III

        • Cutler vs. Kennedy (p605)


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REGULATORY COURSE

  • OTC Drugs (Cont’d)

    • Procedures for classifying OTC drugs at GRAS&E - 21 CFR 330

      • The Legality of Category III

        • Cutler vs. Kennedy (p605)

      • Category III flies in the face of the FD&C 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


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REGULATORY COURSE

  • OTC Drugs (Cont’d)

    • 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


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REGULATORY COURSE

  • OTC Drugs (Cont’d)

    • 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



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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


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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 FD&C Act are sufficient to assure safety and efficacy


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REGULATORY COURSE

  • CLASSIFICATION OF DEVICES:

    • Class II - includes those devices for which general controls that exist under the FD&C Act are not sufficient to assure safety and efficacy, and for which enough information exists to develop a performance standard.


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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.


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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.



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