1. Dullien Associates, LLC
NAVIGATING THE FDA
Vivian K. Dullien, PhD
FDA, Clinical and Business Consultant
Dullien Associates, LLC
Boulder, Colorado
Vivian K. Dullien, Ph.D Dullien Associates, LLC

2. Meet with FDA early in process and keep in touch.
NAVIGATING THE FDA Vivian K. Dullien, PhD

3. Before you meet, do your homework.
NAVIGATING THE FDA Vivian K. Dullien, PhD

4. What are you? Diagnostic Device Drug Biologic Combination
NAVIGATING THE FDA Vivian K. Dullien, PhD

5. What disease?
NAVIGATING THE FDA Vivian K. Dullien, PhD

6. What for? Screening? Diagnosing? Monitoring? Treating?
NAVIGATING THE FDA Vivian K. Dullien, PhD

7. What patient population?
Screen general population
Treat general population
Symptomatic
High risk
Early stage
Late stage
Age group
NAVIGATING THE FDA Vivian K. Dullien, PhD

8. If device or diagnostic, is there a predicate?
Comparison to predicate – where similar, where not
NAVIGATING THE FDA Vivian K. Dullien, PhD

9. Devices: 510(k) or PMA? Determine: Risk level Novelty Predicate
Duration:
510(k): 30+ days
PMA: 1 year
NAVIGATING THE FDA Vivian K. Dullien, PhD

10. The driver in the FDA process – “Indications for Use”
Drug or device?
The driver in the FDA process – “Indications for Use”
Part of product label
NAVIGATING THE FDA Vivian K. Dullien, PhD

11. 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.
NAVIGATING THE FDA Vivian K. Dullien, PhD

12. 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
NAVIGATING THE FDA Vivian K. Dullien, PhD

13. Your FDA studies are to support the claims in your “Indications for Use”
NAVIGATING THE FDA Vivian K. Dullien, PhD

14. “Indications for Use”
Will determine what you can say in marketing material once you have been approved
NAVIGATING THE FDA Vivian K. Dullien, PhD

15. 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?
NAVIGATING THE FDA Vivian K. Dullien, PhD

16. Study endpoints: statistician’s inputs
Study power
N size
Methods to measure statistical significance
NAVIGATING THE FDA Vivian K. Dullien, PhD

17. Survey the market Review similar products on the market
Look at labels, Indications for Use, warnings and limitations
NAVIGATING THE FDA Vivian K. Dullien, PhD

18. 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
NAVIGATING THE FDA Vivian K. Dullien, PhD

19. FDA - organizational On Internet (http://www.fda.gov/opacom/7org.html)
Office of the Commissioner:
Biologics:
Devices and Radiological Health:
Drug Evaluation:
Veterinary Medicine:
Regulatory Affairs:
Food Safety and Applied Nutrition:
NAVIGATING THE FDA Vivian K. Dullien, PhD

20. 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
NAVIGATING THE FDA Vivian K. Dullien, PhD

21. 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)
NAVIGATING THE FDA Vivian K. Dullien, PhD

22. 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
NAVIGATING THE FDA Vivian K. Dullien, PhD

23. 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
NAVIGATING THE FDA Vivian K. Dullien, PhD

24. Phases of device studies
Feasibility
Pivotal
510(k)
PMA
NAVIGATING THE FDA Vivian K. Dullien, PhD

25. 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
NAVIGATING THE FDA Vivian K. Dullien, PhD

26. Detailed description of device
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
NAVIGATING THE FDA Vivian K. Dullien, PhD

27. 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
NAVIGATING THE FDA Vivian K. Dullien, PhD

28. Drug review steps Pre-IND, animal testing
IND – outlines human testing. Meet with FDA before submitting IND. IND reviewed by FDA and IRB
Phase 1: subjects
Phase 2: subjects
Phase 3: several hundred to Meet with FDA before Phase 3
Pre-NDA, meet with FDA before submitting NDA
Submit NDA
Review
Facilities inspected
Approvable or not approvable
NAVIGATING THE FDA Vivian K. Dullien, PhD

29. 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
NAVIGATING THE FDA Vivian K. Dullien, PhD

30. 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
NAVIGATING THE FDA Vivian K. Dullien, PhD

31. Drug clinical stages Phase 1 - healthy volunteers
- Side effects, how drug is metabolized and excreted
- Safety
Phase Patients
- Effectiveness – preliminary information if drug works in humans with the disease
Phase large safety and efficacy studies
- different dosages, drug combinations and populations
NAVIGATING THE FDA Vivian K. Dullien, PhD

32. Timelines – clinical testing of drugs
Range: 2 – 10 years (average 5 – 7 years)
Phase years
Phase years
Phase years
NDA usually 100,000 pages in length, takes at least 6 months to review. Average 2 years (range 2 months to 7 years.)
NAVIGATING THE FDA Vivian K. Dullien, PhD

33. Quality of clinical data
IRB approval, informed consent
Study conducted according to protocol
adverse events recorded
subsets met the inclusion/exclusion criteria
NAVIGATING THE FDA Vivian K. Dullien, PhD

34. 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
NAVIGATING THE FDA Vivian K. Dullien, PhD

35. 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
NAVIGATING THE FDA Vivian K. Dullien, PhD

36. Device or drug
Continuous interaction between FDA and company during review process
NAVIGATING THE FDA Vivian K. Dullien, PhD

37. It all comes down to this:
The package insert
NAVIGATING THE FDA Vivian K. Dullien, PhD

38. Dullien Associates, LLC
Thank you!
Vivian K. Dullien, Ph.D.
Dullien Associates, LLC
(303)
NAVIGATING THE FDA Vivian K. Dullien, PhD