Download navigating the fda

Vivian K. Dullien, PhD
FDA, Clinical and Business Consultant
Dullien Associates, LLC
Boulder, Colorado
Meet with FDA early in process
and keep in touch.
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Before you meet, do your
homework.
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What are you?
• Diagnostic
• Device
• Drug
• Biologic
• Combination
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What disease?
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What for?
• Screening?
• Diagnosing?
• Monitoring?
• Treating?
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What patient population?
• Screen general population
• Treat general population
• Symptomatic
• High risk
• Early stage
• Late stage
• Age group
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If device or diagnostic, is
there a predicate?
Comparison to predicate – where
similar, where not
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Devices: 510(k) or PMA?
Determine:
• Risk level
• Novelty
• Predicate
Duration:
• 510(k): 30+ days
• PMA: 1 year
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Drug or device?
• The driver in the FDA process –
“Indications for Use”
• Part of product label
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Examples of Indication for Use
Drug:
Nasal spray, 50 mcg is indicated for the treatment of the
nasal symptoms of seasonal allergic and perennial allergic
rhinitis in adults and pediatric patients 2 years of age or
older. “X” nasal spray, 50 mcg is indicated for the
prophylaxis of nasal symptoms of seasonal allergic rhinitis
in adult and adolescent patients 12 years and older.
Diagnostic:
“X” culture test is a qualitative in-vitro diagnostic test for
the rapid detection of nasal colonization of staphylococcus
aureus. The test is intended to aid in the prevention and
control of staphylococcus aureus infections in healthcare
settings. The test is not intended to diagnose
staphylococcus aureus infections, nor monitor treatment of
infection.
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Product label can include:
• Description (clinical pharmacology)
• Clinical studies summary
• Indication and usage
• Warnings
• Precautions
• Adverse reactions
• Contra indications
• Dosage and administration
• Information for patients
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Your FDA studies are to support the
claims in your “Indications for Use”
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“Indications for Use”
Will determine what you can say in
marketing material once you have
been approved
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Study endpoints
• How will you measure your safety
and efficacy?
• If device – agreement to predicate –
what is your predicate?
• What is the gold standard?
• Are you an AID in
diagnosing/treating or stand-alone?
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Study endpoints: statistician’s
inputs
• Study power
• N size
• Methods to measure statistical
significance
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Survey the market
• Review similar products on the
market
• Look at labels, Indications for Use,
warnings and limitations
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Ready to approach FDA
• Phone, e-mail
• Set up a face-to-face meeting: pre-IDE or pre-IND
• Send in information before meeting
• Include: product description, predicate
comparison if applicable, suggestion on how to be
classified, indications for use, protocol outline
with study endpoints, suggest N size. If drug
results of animal study safety, pilot/lab, feasibility
results, statistical methods to be used
• List of questions for FDA
• Who will attend
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FDA - organizational
• On Internet (http://www.fda.gov/opacom/7org.html)
• Office of the Commissioner: 301-796-5000
• Biologics: 301-827-0372
• Devices and Radiological Health: 240-276-3939
• Drug Evaluation: 301-796-5400
• Veterinary Medicine: 240- 276-9000
• Regulatory Affairs: 301-827-3101
• Food Safety and Applied Nutrition: 301-436-1600
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FDA meeting & post-meeting
process
• Get FDA feedback and take minutes
• Send minutes to FDA for review
• Incorporate FDA suggestions into
your planned studies
• Send protocol to FDA for review and
comments before you start
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Clinical devices:
Investigation device exemption
(IDE), unless exempt
Need:
• Protocol approved by IRB. If significant risk,
the IDE must be approved by FDA
• Informed consent from patient
• Labeling for investigational use only
• Required records and reports
• Conduct under GCP (21 CFR 812, 50, 56, 54, 820)
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IDE includes:
• Device name and description
• Device intended use
• Sponsor contact information
• Manufacturer information
• Laboratory studies
• Reports of animal studies
• Prior publications
• Investigational plan, including protocol, risk analysis,
monitoring procedures, list of investigators, IRB’s,
informed consents
• Labeling
• Description of methods, facilities and controls used for
manufacture, processing, packing, storage, installation
of device
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IDE exempt:
• Non-invasive
• Does not require invasive sampling that
presents significant risk
• Does not introduce energy into a subject
• Is not used as a diagnostic procedure, without
confirmation of another medically established
product or procedure
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Phases of device studies
• Feasibility
• Pivotal
• 510(k)
• PMA
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Pre-IDE process
• Informal guidance meeting (before IDE
submitted): help with development of protocol,
supporting pre-clinical data. Can be telephone
conference calls, video conference, or face-to-face
• Formal guidance meeting: determination
meeting – written request to review intended use,
protocol, and type of valid scientific evidence
required. A pre-IDE submission
• Agreement meeting – written request to reach
agreement with FDA regarding FDA’s review of the
clinical protocol and investigational plan
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Agreement meeting written request:
• Detailed description of device
• Detailed description of proposed conditions of
use of device
• Proposed plan (including clinical protocol)
• Information regarding expected performance
Agreement put in writing
Keep in contact with FDA throughout process
from informal to formal agreement meetings
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Additional guidances can be
found:
• Early collaboration meetings
• Goals and initiatives for the IDE
program
• Pre-IDE program: “Issues and Answers”
• Search Internet and find guidances.
• FDA has put guidances on the Internet
for devices and drugs
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Drug review steps
1. Pre-IND, animal testing
2. IND – outlines human testing. Meet with FDA
before submitting IND. IND reviewed by FDA and
IRB
3. Phase 1: 20-80 subjects
4. Phase 2: 12-300 subjects
5. Phase 3: several hundred to 3000. Meet with FDA
before Phase 3
6. Pre-NDA, meet with FDA before submitting NDA
7. Submit NDA
8. Review
9. Facilities inspected
10. Approvable or not approvable
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Pre-clinical testing in animals
•
•
•
Assessing toxicity in single doses of increasing strength, 2+
species
Different routes of administration
Determine ED50, LD50, duration of effects
Subjects autopsied for cause of death
Sub-acute toxicity
3 or more routes of administration
3 different dose levels, 2+ species, observed 2 – 12 weeks
Estimate what human dosages will be
Especially note liver, kidneys and nervous system
Chronic toxicity
3 – 24 months
At least 6 months before human studies
Carcinogenic effects, 6 months, 2+ species, same route of
administration as humans
Teratogenic effects
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IND contents include:
• Pre-clinical toxicology and pharmacology
results
• Phase 1 protocols
• Drug facilities, processes, articles used in
manufacturing, processing, packaging, and
storing drugs for humans
• Chemistry, manufacturing and control
information
• Previous experience with human subjects
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Drug clinical stages
• Phase 1
- healthy volunteers
- Side effects, how drug is
metabolized and excreted
- Safety
• Phase 2 - Patients
- Safety
- Effectiveness – preliminary
information if drug works in humans
with the disease
• Phase 3 - large safety and efficacy studies
- different dosages, drug
combinations and populations
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Timelines – clinical testing of
drugs
Range: 2 – 10 years (average 5 – 7 years)
• Phase 1 1 + years
• Phase 2 2 + years
• Phase 3 3 + years
NDA usually 100,000 pages in length, takes at
least 6 months to review. Average 2 years (range 2
months to 7 years.)
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Quality of clinical data
• IRB approval, informed consent
• Study conducted according to protocol
• adverse events recorded
• subsets met the inclusion/exclusion
criteria
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Reviewing applications for drug or
device
FDA review team - medical doctors, chemists,
statisticians, microbiologists,
pharmacologists and other
experts
- determine if drug/device is
safe and effective for its
proposed use
Each reviewer prepares written evaluations that are
considered by team leaders, division directors, office
directors, depending on type of application
•
Sometimes FDA calls upon advisory committees
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Issues that can arise
• Clinical data not supportive of indications for use –
need more data
•Inadequacy on how people respond to various
dosages – need more data
•“Approvable” – probably be approved, provided
certain issues get resolved
•Labeling
•Safety issues
•Manufacturing issues – can delay or deny
application. Product that is going to be marketed is
the same product that was tested
•Depending on FDA action – meet to discuss
deficiencies, ask for hearing, correct deficiencies,
submit new information or withdraw application
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Device or drug
Continuous interaction between
FDA and company during review
process
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It all comes down to this:
The package insert
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Thank you!
Vivian K. Dullien, Ph.D.
Dullien Associates, LLC
[email protected]
(303) 499-6777
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