NAVIGATING THE FDA

NAVIGATING THE FDAVivian K. Dullien, PhDFDA, Clinical and Business ConsultantDullien Associates, LLCBoulder, Colorado

1Vivian K. Dullien, Ph.D. Dullien Associates, LLCNAVIGATING THE FDA Vivian K. Dullien, PhDMeet with FDA early in process and keep in touch.2NAVIGATING THE FDA Vivian K. Dullien, PhDBefore you meet, do your homework.3NAVIGATING THE FDA Vivian K. Dullien, PhDWhat are you?

Diagnostic Device Drug Biologic Combination4NAVIGATING THE FDA Vivian K. Dullien, PhDWhat disease?5NAVIGATING THE FDA Vivian K. Dullien, PhDWhat for?

Screening? Diagnosing? Monitoring? Treating?6NAVIGATING THE FDA Vivian K. Dullien, PhDWhat patient population?

Screen general population Treat general population Symptomatic High risk Early stage Late stage Age group7NAVIGATING THE FDA Vivian K. Dullien, PhDIf device or diagnostic, is there a predicate?

Comparison to predicate where similar, where not8NAVIGATING THE FDA Vivian K. Dullien, PhDDevices: 510(k) or PMA?Determine: Risk level Novelty Predicate

Duration: 510(k): 30+ days PMA: 1 year

9NAVIGATING THE FDA Vivian K. Dullien, PhDDrug or device?

The driver in the FDA process Indications for Use

Part of product label10NAVIGATING THE FDA Vivian K. Dullien, PhDExamples of Indication for UseDrug: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.11NAVIGATING THE FDA Vivian K. Dullien, PhDProduct label can include: Description (clinical pharmacology) Clinical studies summary Indication and usage Warnings Precautions Adverse reactions Contra indications Dosage and administration Information for patients12NAVIGATING THE FDA Vivian K. Dullien, PhDYour FDA studies are to support the claims in your Indications for Use13NAVIGATING THE FDA Vivian K. Dullien, PhDIndications for Use

Will determine what you can say in marketing material once you have been approved14NAVIGATING THE FDA Vivian K. Dullien, PhDStudy 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?15NAVIGATING THE FDA Vivian K. Dullien, PhDStudy endpoints: statisticians inputs

Study power N size Methods to measure statistical significance16NAVIGATING THE FDA Vivian K. Dullien, PhDSurvey the market

Review similar products on the market Look at labels, Indications for Use, warnings and limitations17NAVIGATING THE FDA Vivian K. Dullien, PhDReady 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

18NAVIGATING THE FDA Vivian K. Dullien, PhDFDA - 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

19NAVIGATING THE FDA Vivian K. Dullien, PhDFDA 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

20NAVIGATING THE FDA Vivian K. Dullien, PhDClinical 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)

21NAVIGATING THE FDA Vivian K. Dullien, PhDIDE 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, IRBs, informed consents Labeling Description of methods, facilities and controls used for manufacture, processing, packing, storage, installation of device

22NAVIGATING THE FDA Vivian K. Dullien, PhDIDE 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

23NAVIGATING THE FDA Vivian K. Dullien, PhDPhases of device studies

Feasibility Pivotal 510(k) PMA

24NAVIGATING THE FDA Vivian K. Dullien, PhDPre-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 FDAs review of the clinical protocol and investigational plan

25NAVIGATING THE FDA Vivian K. Dullien, PhDAgreement 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

26NAVIGATING THE FDA Vivian K. Dullien, PhDAdditional 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

27NAVIGATING THE FDA Vivian K. Dullien, PhDDrug review stepsPre-IND, animal testing IND outlines human testing. Meet with FDA before submitting IND. IND reviewed by FDA and IRBPhase 1: 20-80 subjectsPhase 2: 12-300 subjectsPhase 3: several hundred to 3000. Meet with FDA before Phase 3Pre-NDA, meet with FDA before submitting NDASubmit NDAReviewFacilities inspectedApprovable or not approvable

28NAVIGATING THE FDA Vivian K. Dullien, PhDPre-clinical testing in animalsAssessing toxicity in single doses of increasing strength, 2+ speciesDifferent routes of administrationDetermine ED50, LD50, duration of effectsSubjects autopsied for cause of death Sub-acute toxicity3 or more routes of administration3 different dose levels, 2+ species, observed 2 12 weeksEstimate what human dosages will beEspecially note liver, kidneys and nervous systemChronic toxicity3 24 monthsAt least 6 months before human studiesCarcinogenic effects, 6 months, 2+ species, same route of administration as humansTeratogenic effects

29NAVIGATING THE FDA Vivian K. Dullien, PhDIND 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

30NAVIGATING THE FDA Vivian K. Dullien, PhDDrug 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

31NAVIGATING THE FDA Vivian K. Dullien, PhDTimelines 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.)

32NAVIGATING THE FDA Vivian K. Dullien, PhDQuality of clinical data

IRB approval, informed consent Study conducted according to protocol adverse events recorded subsets met the inclusion/exclusion criteria

33NAVIGATING THE FDA Vivian K. Dullien, PhDReviewing 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 useEach 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

34NAVIGATING THE FDA Vivian K. Dullien, PhDIssues that can arise Clinical data not supportive of indications for use need more dataInadequacy on how people respond to various dosages need more dataApprovable probably be approved, provided certain issues get resolvedLabelingSafety issuesManufacturing issues can delay or deny application. Product that is going to be marketed is the same product that was testedDepending on FDA action meet to discuss deficiencies, ask for hearing, correct deficiencies, submit new information or withdraw application

35NAVIGATING THE FDA Vivian K. Dullien, PhDDevice or drug

Continuous interaction between FDA and company during review process

36NAVIGATING THE FDA Vivian K. Dullien, PhDIt all comes down to this:

The package insert

37NAVIGATING THE FDA Vivian K. Dullien, PhDThank you!

Vivian K. Dullien, Ph.D.Dullien Associates, LLCDullienV@comcast.net(303) 499-6777

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