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Development of Therapeutic and Diagnostic Products for the U'S' Market


Preparation of New Drug Application (NDA) or Biologics License Application (BLA) ... Your guide through the regulatory maze. As patent term expires: ... – PowerPoint PPT presentation

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Title: Development of Therapeutic and Diagnostic Products for the U'S' Market

Development of Therapeutic and Diagnostic
Products for the U.S. Market
  • Jill B. DealFish Richardson P.C.deal_at_fr.comht
    tp// 626-6429

Summary of presentation
  • Development of a therapeutic
  • Which center at FDA will review your product?
  • Development of a diagnostic
  • Compensation for developmental/regulatory delays
  • Role of regulatory

Developing a therapeutic product
  • The risks
  • Less than 1 of issued patents result in products
    that undergo clinical trials
  • Less than .4 of clinically tested patents makes
    it to market
  • Fewer than 1 out of 25,000 drug patents make it
    to market
  • Costs average 350 million
  • Time average 8-10 years to bring to market

  • Prozac and Prilosec - 1996 - 4.75 million/day
  • Zantac and Zovirax/Glaxo-Wellcome and the
    proposed SKB merger

New Drug Development Timeline
Pre-Clinical Testing, Research Development
Post-Marketing Surveillance
NDA Review
Clinical Research Development
Range 1-3 yearsAverage 18 months Initial
Synthesis AnimalTesting
Range 2-10 years Average 5 years
Range 2 months-7 years Average 24 months
Adverse Reaction Reporting Surveys/Sampling/
Testing Inspections
Phase 1
Phase 2
Phase 3
Short Term
30-Day Safety Review
FDA Time
NDA Submitted
Industry Time
Source FDA
Pre-clinical testing and research
FDA involvement indirect through guidance and
  • On substance
  • Chemical assays
  • Computer modeling
  • Fermentation broths
  • Goal
  • Possible effect on body
  • On substance in animals
  • 2 or more species
  • Pharmacological tests
  • Toxicity tests
  • Short-term studies
  • Goal
  • What does the body do to the drug?
  • Absorption/bioavailability
  • Distribution
  • Metabolism
  • Excretion
  • (ADME)

Clinical testing on human beings
FDA/Institutional Review Board (IRB) Involved
  • Phase I (healthy volunteers)
  • 20-80 subjects
  • Goal
  • Identify most common adverse effects
  • Identify safe dosage range
  • Absorption, distribution, metabolization,
    excretion, duration in humans

Clinical testing on human beings
FDA/IRB involved
  • Phase II
  • 100-300 patients
  • Goal
  • Establish safety and efficacy of substance in
    patients with disease or condition

The importance of controlled clinical trials
Placebo Controlled
Another drug/another dose of study drug
Placebo arm
Drug arm
Blinded - single blinded (patients) Randomized -
minimization of selection bias Double-blinded -
only code-breakers know
Historical control
  • Patients given drug
  • Other patients given drug at a different time or
  • About same time at other institutionsor
  • Patients followed after trial before and after
    treatment with drug

Controlled trials
  • Internal controls
  • All patients have same disease
  • All patients at same stage of disease
  • Similar weight, age
  • Other medical treatment same
  • Informed consent
  • Ethical issues
  • Add-on studies (treatment and new drug), seizures
    heart attacks)
  • Historical exclusion of women and children -
  • Pediatric studies - Food Drug Modernization Act
    of 1997 (FDAMA)
  • 1993 FDA Guidance on inclusion of women
  • Protocol drafted to ensure that conditions of
    administration same

Clinical testing on human beings
FDA/IRB involved
  • Phase III
  • 1,000-3,000 patient volunteers
  • Goal
  • Establish safety and efficacy in a larger patient

Other tests and trials during Phase II and III
FDA/IRB involved
  • Animals
  • Long-term studies
  • Toxicity
  • Reproductive effects
  • Humans
  • Pharmacodynamics
  • Pharmacokinetics
  • Reproductive effects
  • Impact on special groups (children, elderly,
    pregnant women)
  • Drug/drug interactions
  • Abusive potential
  • Combination trials

Other issues arising during Phase III
FDA involved
  • Preparation of New Drug Application (NDA) or
    Biologics License Application (BLA)
  • Registration/listing issues
  • Scale up to Good Manufacturing Practice standards
    for commercial production
  • Labeling issues
  • Promotional issues
  • Managed care issues
  • Prepare for FDA GMP inspection

Prescription Drug User Fee Act of 1992 (PDUFA)
  • Renewed by Food and Drug Administration
    Modernization Act of 1997 (FDAMA)
  • User fees for applications
  • Establishment fees
  • Goal To expedite processing of NDAs/BLAs

PDUFA/FDAMA user fees
  • Full application
  • 205,704 - FY98 258,451- FY2002
  • Other applications
  • 125,352 - FY99 129,226 - FY2002
  • Establishment fees fee revenues to FDA at
    35,600,000 FY98 36,700,000 - FY2002
  • Waivers/exemptions
  • NDA for orphan drug
  • Supplements for pediatric applications
  • Small businesses for first human drug application
    (fewer than 500 employees) (upon application)

Final issues
Establishment Listing/Registration NDA/BLA
NDA/BLA approval
  • Phase IV studies
  • internal controls affect external validity
  • Pharmacological studies for reimbursement
  • New dosage forms
  • New indications

FDA involved
Establishment inspection
Which Center at FDA will regulate your products?
Combination products
  • Primary action as device? - CDRH
  • Primary action as biologic? - CBER
  • Primary action as drug? - CDER

Read the Memoranda of Understanding!Determine
primary jurisdiction in advance!Are there
advantages in being regulated as a drug or
biologic? (e.g., Hatch/Waxman issues)
The importance of FDA compliance
  • Adulteration and misbranding
  • Sections 501 and 502 of the Federal Food, Drug
    Cosmetic Act
  • Refuse to file
  • Refuse to approve
  • Warning letter
  • Order to cease distribution
  • Recalls
  • Repair, replace, refund
  • Administrative detention
  • Criminal actions
  • Fines
  • Jail

In Vitro Diagnostic Medical Devices (IVDs)
  • Register establishment and list devices unless
  • Definition of IVD - any healthcare product that
    does not achieve its principle intended purpose
    by chemical action in or on the body or by being
  • Classification
  • Class I - General Controls, registration,
    record-keeping, labeling, compliance with Good
    Manufacturing Practices Regulations
  • Class II - Special Controls - devices for which
    general controls will not ensure safety and
    effectiveness, e.g., performance standards,
    post-market surveillance, patient registries,
  • Class III - implanted and life supporting and
    sustaining devices which must have FDA approval
    unless FDA determines otherwise

Exempt devices
  • Research use
  • See 63 Fed. Reg. 235 (January 5, 1998)
  • Exempted by FDA
  • See 21 CFR 862 (clinical chemistry and clinical
    toxicology devices)21 CFR 864 (hematology and
    pathology devices)21 CFR 866 (immunology and
    microbiology devices)63 Fed. Reg. 3142 (January
    21, 1998)63 Fed. Reg. 5387 (Feb. 2, 1998)

Class I, II or III devices
Class I General controls Class II 510(k)
clearance - substantially equivalent to a
pre-76 device Class III Pre-Market Approval
  • How to classify your device
  • 1. Find a Class I device that is substantially
    equivalent and apply general controls specified
  • 2. Find a substantially equivalent device/devices
    - use for 510(k) and classification purposes
  • 3. PMA approval - FDAMA amendments
  • No longer PMA/Class III automatic default
  • New procedure
  • No recommended classification
  • FDA to classify within 60 days/publish
    classification in Federal Register within 30

Compliance information
  • 21 CFR Part 800
  • Supplemented by Statement of Basis and Purpose
    for Regulations published in the Federal Register
  • Guidance, guidelines
  • Letters to industry
  • Public Health Notices
  • International and national standards recognized
    by FDA pursuant to FDAMA
  • Safety alerts
  • CBER - biologicals, blood and blood-related

increasingly important
Clinical trials of IVDs - exemptions
  • All devices
  • 1. Veterinary use
  • 2. Research on lab animals but cg. 63 Fed. Reg.
    235 (Jan. 5, 1998)
  • 3. Custom device
  • 4. Devices undergoing consumer preference
    testing/testing for modification or a combination
    of two devices in commercial distribution (no
    effect on safety/effectiveness/no risk to
  • 5. Diagnostic devices
  • Properly labeled for research use only, see 21
    CFR 809.10(c)
  • Not an invasive procedure that involves
    significant risk
  • 6. Does not introduce energy into subject
  • 7. Confirmatory of another diagnosis by an
    approved IVD

for a use of substantial importance in
diagnosing a diseaseand presents a potential for
serious risk to the health, safety, or welfare of
a subject
Compensation for regulatory delay
Patentees of products subject to FDA review are
uniquely disadvantaged
Patent filed
Patent issuedRegulatory review preparation begins
??? years
Regulatory review completedCommercialization
Compensating patentees for regulatory delays in
the U.S. and the European Union (EU)
  • Patent term extensions
  • Data exclusivity
  • Orphan exclusivity
  • Hatch/Waxman Act in U.S. Supplementary Protection
    Certificates in EU
  • Hatch/Waxman Act in U.S.FDA Modernization Act of
    1997 (pediatric uses)Article 4(8)(a) of EU
    Directive 65/65/EEC
  • U.S. Orphan Drug Act Upcoming EU legislation

Role of regulatory-Your guide through the
regulatory maze
Role of regulatory-Your guide through the
regulatory maze
Clinical - FDA-related
Role of regulatory-Your guide through the
regulatory maze
Post-Market Vigilance
  • As patent term expires
  • Advice on protecting market share
  • Possible Citizens Petition
  • Litigation assistance in infringement suit
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