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

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

• Jill B. DealFish Richardson P.C.deal_at_fr.comht
  tp//www.fr.com/reg202 626-6429

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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

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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

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Why?

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

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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
Long-Term
30-Day Safety Review
FDA Time
NDA Submitted
NDAApproved
Industry Time
Source FDA
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Pre-clinical testing and research
FDA involvement indirect through guidance and
regulations

• 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)

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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

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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

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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
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Historical control

• Patients given drug

• Other patients given drug at a different time or
  placeor
• About same time at other institutionsor
• Patients followed after trial before and after
  treatment with drug

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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 -
  liability
• 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

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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
  population

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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

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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

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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

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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)

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Final issues
Establishment Listing/Registration NDA/BLA
Application
NDA/BLA approval

• Phase IV studies
• internal controls affect external validity
• Pharmacological studies for reimbursement
  purposes
• New dosage forms
• New indications

FDA involved
Establishment inspection
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Which Center at FDA will regulate your products?
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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)
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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

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In Vitro Diagnostic Medical Devices (IVDs)

• Register establishment and list devices unless
  exempt
• 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
  metabolized
• 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,
  guidelines
• Class III - implanted and life supporting and
  sustaining devices which must have FDA approval
  unless FDA determines otherwise

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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)

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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
(PMA)

• 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
  days

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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
  products

increasingly important
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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
  subjects)
• 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
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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
begins
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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

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Role of regulatory-Your guide through the
regulatory maze
Pre-Clinical
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Role of regulatory-Your guide through the
regulatory maze
Clinical - FDA-related
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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