FDA Legal & Regulatory Considerations for Biomedical Startups

1. FDA Legal & RegulatoryConsiderations for Biomedical Startups Tech Coast Angels San Diego, California March 7, 2003 FDACounsel.com

2. Michael A. Swit, Esq. Michael A. Swit, Esq. Law Offices of Michael A. Swit 539 Samuel Ct. Encinitas, CA 92024 760-815-4762; fax: 760-454-2979 mswit@fdacounsel.com FDACounsel.com

3. Establish FDA Strategy Early!! • Some considerations follow . . . FDACounsel.com

4. FDA's Three Key Development Roles: • "Gatekeeper" to the marketplace -- the new drug approval process • "Cop on the beat" or "Enforcer" -- ensuring quality compliance via inspection and enforcement actions (e.g. criminal charges) • "Sentinel" of Safety Concerns - during development and post-approval FDACounsel.com

5. The Approval Gate … • Preliminary Considerations -- Determining the Regulatory Status of the product • Is it a "drug", "device" or "biologic"? • Drug: • described in USP or • intended (via labeling) • to affect the body of man or other animals • to be used in the diagnosis, cure, mitigation, treatment or prevention of disease in man or other animals FDACounsel.com

6. The Approval Gate … • Regulatory Status of the product - con'd… • Is it a "drug", "device" or "biologic"? • Device: defined as involving: "instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or "similar or related article including any component, part or accessory." • in USP/NF or • intended to be used in diagnosis … cure, mitigation, treatment or prevention of disease or other conditions • intended to affect the body of man FDACounsel.com

7. The Approval Gate … • Regulatory Status of the product - con'd… • Is it a "drug", "device" or "biologic"? • Thus -- device definition can capture products that resemble drugs if they do not achieve their result via being metabolized in the body or via chemical action within or on the body -- regulated by FDA Center for Devices & Radiological Health (CDRH) • Examples of "drug-like" devices: • Ultrasound contrast media • Contact lens solutions FDACounsel.com

8. The Approval Gate … • Regulatory Status of the product - con'd… • Is it a "drug", "device" or "biologic"? • Biologic -- • Generally, if derived from human or animal tissue; • used to be regulated by FDA Center for Biologics (CBER) using approval standards similar to CDER • therapeutic biotech products going to CDER • vaccines – remain behind • NOTE: "true" biotech products usually are biologics FDACounsel.com

9. The Approval Gate … • Regulatory Status of the product - con'd… • Is it a "drug", "device" or "biologic"? • OR BOTH?? • "Combination" or "hybrid" products -- • are regulated per their "primary mode of action" -- • but this may be difficult to discern -- get clarification very early as will impact FDA Center you deal with • can request in writing -- under FDAMA § 416, FDA can't later change its mind w/o your consent or public health reasons exist FDACounsel.com

10. The Approval Gate … • Regulatory Status of the product - con'd… • What type of submission is needed to get FDA approval or clearance? • Drugs: • Full New Drug Application (NDA) • 505(b)(2) NDA or "Paper NDA" • Abbreviated New Drug Application • The OTC Drug route -- Abreva (Avanir/SKB) • NDA • OTC Review monograph change FDACounsel.com

11. The Approval Gate … • Regulatory Status of the product - con'd… • What type of submission is needed to get FDA approval or clearance? • Devices: • Premarket Approval Application (PMA) -- clinical studies will be needed • Premarket Notification under § 510k -- clinical studies MAY be needed (or wanted) FDACounsel.com

12. The Approval Gate … • Regulatory Status of the product - con'd… • What type of submission is needed to get FDA approval or clearance? • Biologics • Biologic License Application (BLA) • no generic versions now possible – may change … FDACounsel.com

13. The Approval Gate … • Regulatory Status of the product - con'd… • What quantity and quality of data will be demanded by FDA to show safety & effectiveness? • Will vary -- FDA has extensive discretion here • Key task -- try to get clarity as soon as possible in the process -- Ways to do so: • Pre-IND meeting -- encouraged by FDA prior to start of human clinicals • End of Phase 2 Meeting - also encouraged -- here's where you want to "lock" them in FDACounsel.com

14. The Approval Gate … • Regulatory Status of the product - con'd… • What quantity and quality of data? • FDAMA § 119(a) -- • FDA must meet with you on design of studies; and • Any agreement on study design must be written and can't be changed later w/o your consent unless a new safety or effectiveness issue arises later FDACounsel.com

15. The Approval Gate … • Regulatory Status of the product - con'd… • What quantity and quality of data? • FDAMA § 115(a) -- data from must one adequate and well-controlled study and confirmatory evidence can be used to show substantial evidence of effectiveness FDACounsel.com

16. The Approval Gate … • Regulatory Status of the product - con'd… • What quantity and quality of data? • "Pure" proof of clinical effectiveness may not be needed -- e.g., under “Fast Track,” may be able to use: • Surrogate endpoints • Clinical endpoints • Phase IV study will be needed usually FDACounsel.com

17. The Approval Gate … • FDA -- Legal Barriers to entry • Orphan Drug Exclusivity -- 7 years for drug for orphan indication • can't "remake the wheel" • Waxman-Hatch Exclusivity • 5 years -- New Chemical Entities • 3 years -- New uses, dosage forms, etc. of previously-approved products FDACounsel.com

18. The Approval Gate … • The FDA Review -- Priority and Speed • "Fast Track" -- FDAMA § 112 • treats a "serious or life threatening condition" • shows "potential to address unmet medical needs for such condition" • If so, FDA must "facilitate the development and expedite and review" of the drug • Request at time of or after IND filing • See 1998 Guidance on Fast Track • http://www.fda.gov/cder/guidance/2112fnl.pdf FDACounsel.com

19. The Approval Gate … • The FDA Review -- Priority and Speed • General NDA classification system • 1 -- New molecular entity • 2 -- New Salt of Previously Approved Drug (not a new molecular entity) • 3 -- New Formulation of Previously Approved Drug (not a new salt OR a new molecular entity) • 4 -- New Combination of Two or More Drugs • 5 -- Already Marketed Drug Product - Duplication (i.e., new manufacturer) FDACounsel.com

20. The Approval Gate … • The FDA Review -- Priority and Speed • General NDA classification system • 6 -- New Indication (claim) for Already Marketed Drug (includes switch in marketing status from prescription to OTC) • 7 -- Already Marketed Drug Product - No Previously Approved NDA (e.g., Unithroid) • NDA Review Priority: • S - Standard -- drugs similar to currently available drugs • P - Priority -- significant advances over existing treatments. FDACounsel.com

21. The Approval Gate … • The FDA Review -- Pre-Approval Inspections -- Expect one if NDA is: • new chemical or molecular entities; • for a narrow therapeutic range drug • the first approval for the applicant; or • are sponsored by a company with a history of CGMP problems or that has not been inspected for a considerable period. • CDER's Compliance Program Guide 7346.832 @ • http://www.fda.gov/cder/handbook/insaccep.htm FDACounsel.com

22. The Approval Gate … • A few tips to avoid problems in drug development and speed FDA review: • If outsourcing, audit aggressively your "vendors": • CROs • Clinical investigators • Contract manufacturers • IRBs • Duke • University of Oklahoma • Joint venture partners FDACounsel.com

23. The Approval Gate … • Tips to avoid problems & speed review… • Make sure R&D and Sales & Marketing are talking early on -- ensure the indication being studied is one you want to sell • If planning to get Medicare reimbursement, make sure: • start the reimbursement qualification process early • study your drug in Medicare-age patients FDACounsel.com

24. The Approval Gate … • Tips to avoid problems & speed review… • Study and File electronically • Respond to FDA deficiency letters during review promptly, fully, and honestly • remember -- there are these folks called products liability plaintiffs lawyers and Securities class actions folks waiting for you to make a mistake • Don't bury your head to problems -- investigate and disclose promptly FDACounsel.com

25. The Approval Gate … • Hopefully, will open for you!! • But the odds are long, the cost is high, and the time is lengthy • Good luck!! FDACounsel.com