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Vivian K. Dullien, PhD FDA, Clinical and Business Consultant Dullien Associates, LLC Boulder, Colorado Slide 2 NAVIGATING THE FDA Vivian K. Dullien, PhD Meet with FDA early in process and keep in touch. 2 Slide 3 NAVIGATING THE FDA Vivian K. Dullien, PhD Before you meet, do your homework. 3 Slide 4 NAVIGATING THE FDA Vivian K. Dullien, PhD What are you? Diagnostic Device Drug Biologic Combination 4 Slide 5 NAVIGATING THE FDA Vivian K. Dullien, PhD What disease? 5 Slide 6 NAVIGATING THE FDA Vivian K. Dullien, PhD What for? Screening? Diagnosing? Monitoring? Treating? 6 Slide 7 NAVIGATING THE FDA Vivian K. Dullien, PhD What patient population? Screen general population Treat general population Symptomatic High risk Early stage Late stage Age group 7 Slide 8 NAVIGATING THE FDA Vivian K. Dullien, PhD If device or diagnostic, is there a predicate? Comparison to predicate where similar, where not 8 Slide 9 NAVIGATING THE FDA Vivian K. Dullien, PhD Devices: 510(k) or PMA? Determine: Risk level Novelty Predicate Duration: 510(k): 30+ days PMA: 1 year 9 Slide 10 NAVIGATING THE FDA Vivian K. Dullien, PhD Drug or device? The driver in the FDA process Indications for Use Part of product label 10 Slide 11 NAVIGATING THE FDA Vivian K. Dullien, PhD 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. 11 Slide 12 NAVIGATING THE FDA Vivian K. Dullien, PhD 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 12 Slide 13 NAVIGATING THE FDA Vivian K. Dullien, PhD Your FDA studies are to support the claims in your Indications for Use 13 Slide 14 NAVIGATING THE FDA Vivian K. Dullien, PhD Indications for Use Will determine what you can say in marketing material once you have been approved 14 Slide 15 NAVIGATING THE FDA Vivian K. Dullien, PhD 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? 15 Slide 16 NAVIGATING THE FDA Vivian K. Dullien, PhD Study endpoints: statisticians inputs Study power N size Methods to measure statistical significance 16 Slide 17 NAVIGATING THE FDA Vivian K. Dullien, PhD Survey the market Review similar products on the market Look at labels, Indications for Use, warnings and limitations 17 Slide 18 NAVIGATING THE FDA Vivian K. Dullien, PhD 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 18 Slide 19 NAVIGATING THE FDA Vivian K. Dullien, PhD FDA - organizational On Internet (http://www.fda.gov/opacom/7org.html )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 19 Slide 20 NAVIGATING THE FDA Vivian K. Dullien, PhD 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 20 Slide 21 NAVIGATING THE FDA Vivian K. Dullien, PhD 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) 21 Slide 22 NAVIGATING THE FDA Vivian K. Dullien, PhD 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, IRBs, informed consents Labeling Description of methods, facilities and controls used for manufacture, processing, packing, storage, installation of device 22 Slide 23 NAVIGATING THE FDA Vivian K. Dullien, PhD 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 23 Slide 24 NAVIGATING THE FDA Vivian K. Dullien, PhD Phases of device studies Feasibility Pivotal 510(k) PMA 24 Slide 25 NAVIGATING THE FDA Vivian K. Dullien, PhD 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 FDAs review of the clinical protocol and investigational plan 25 Slide 26 NAVIGATING THE FDA Vivian K. Dullien, PhD 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 26 Slide 27 NAVIGATING THE FDA Vivian K. Dullien, PhD 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 27 Slide 28 NAVIGATING THE FDA Vivian K. Dullien, PhD 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 28 Slide 29 NAVIGATING THE FDA Vivian K. Dullien, PhD 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 29 Slide 30 NAVIGATING THE FDA Vivian K. Dullien, PhD 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 30 Slide 31 NAVIGATING THE FDA Vivian K. Dullien, PhD 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 31 Slide 32 NAVIGATING THE FDA Vivian K. Dullien, PhD 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.) 32 Slide 33 NAVIGATING THE FDA Vivian K. Dullien, PhD Quality of clinical data IRB approval, informed consent Study conducted according to protocol adverse events recorded subsets met the inclusion/exclusion criteria 33 Slide 34 NAVIGATING THE FDA Vivian K. Dullien, PhD 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 34 Slide 35 NAVIGATING THE FDA Vivian K. Dullien, PhD 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 35 Slide 36 NAVIGATING THE FDA Vivian K. Dullien, PhD Device or drug Continuous interaction between FDA and company during review process 36 Slide 37 NAVIGATING THE FDA Vivian K. Dullien, PhD It all comes down to this: The package insert 37 Slide 38 NAVIGATING THE FDA Vivian K. Dullien, PhD Thank you! Vivian K. Dullien, Ph.D. Dullien Associates, LLC DullienV@comcast.net (303) 499-6777 38