FDA Regulatory Considerations for the Biomedical Start-Up Michael A. Swit, Esq. Vice President, Life Sciences LARTA CAP Program Newport Beach, CA October 7, 2005

Establish FDA Strategy Early!! Some considerations follow...

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

Regulatory Status – 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

Regulatory Status – 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

Regulatory Status – Drug, Device or Biologic? … 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 –Oral rinse used as barrier to plaque formation

7 Regulatory Status – Drug, Device or Biologic? … Devices … –Risk of device determines how regulated Class I – simplest – “General Controls” Class II – more risky – “Special Controls” Class III – most risky – Premarket Approval required –Problem – totally new technology is automatically placed in Class III Can petition to take out of Class III if you don’t think the new technology is “risky”

Regulatory Status – Drug, Device or Biologic? Biologics -- –Generally, if derived from human or animal tissue –Not, technically, approved under Federal Food, Drug & Cosmetic Act; but under Public Health Service Act –Therapeutic biologics -- were regulated by FDA Center for Biologics (CBER) using approval standards similar to CDER therapeutic biotech products now at CDER vaccines – remain behind NOTE: "true" biotech products usually are biologics

Regulatory Status – Drug, Device or Biologic? Is it a “drug,” “device” or “biologic” … or both? "Combination" or "hybrid" products -- –are regulated per their "primary mode of action" (“PMOA”) –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 –FDA -- final rule on “PMOA” – Sept. 2005

Type of Submission Required for FDA Approval or Clearance Drugs: –Full New Drug Application (NDA) –505(b)(2) NDA or "Paper NDA“ – can be avenue for “innovative” products based on already-approved ingredients –Abbreviated New Drug Application –The OTC Drug route -- Rx/OTC Switch OTC Review monograph change NDA – direct to OTC -- very rare – Abreva® (Avanir/SKB)

Type of Submission Required for FDA Approval or Clearance Devices: –Premarket Approval Application (PMA) – Class III devices clinical studies will be needed – efficacy and safety detailed safety data –Premarket Notification under § 510k – Class II (most) and some Class I devices Standard – “substantial equivalence” to a lawfully marketed product – thus, technically, you are not proofing either safety or effectiveness. clinical studies MAY be needed (or wanted)

Type of Submission Required for FDA Approval or Clearance Biologics –Biologic License Application (BLA) – covers both Product Facility –Generic versions not possible – may change …

What Data – Quantity & Quality – Will FDA Require? 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

What Data – Quantity & Quality – Will FDA Require? 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 –“Special Protocol Assessments” – FDA process for implementing FDAMA § 115(a) -- data from one adequate and well- controlled study and confirmatory evidence can be used to show substantial evidence of effectiveness

What Data – Quantity & Quality – Will FDA Require? … "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

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

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)

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.

19 The FDA Review -- Priority and Speed Vioxx Backlash – –FDA – Now Very Risk adverse Slower Leadership fragmented – Crawford resignation –“New” or “Renewed” “Regulators” Congress Products Liability Lawyers U.S. Attorneys States Attorney General “Qui Tam” relators

FDA-Enforced Barriers to Entry Orphan Drug Exclusivity -- 7 years for orphan drug for orphan indication –can't "remake the wheel“ –Does not block non-orphan indications Waxman-Hatch Exclusivity –5 years -- New Chemical Entities –3 years -- New uses, dosage forms, etc. of previously- approved products New indications – less useful to prevent generic competition

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 Understand, that an approval is not enough – you need to get Medicare &/or private payer reimbursement –Start the reimbursement qualification process early –Design clinical protocols to address payer expectations Private & Government Example -- study your drug in Medicare-age patients

Tips to avoid problems & speed review… Make sure you are ready to go to “D” from “R” – –Internally – people and systems –Formulation has been rigorously reviewed so as to optimize your chances when going into humans Study and file electronically, if possible Respond to FDA deficiency letters during review promptly, fully, and honestly –Know how the system works – if you don’t agree with a reviewer’s decision, work up the chain of command

Tips to avoid problems & speed review… If outsourcing, audit aggressively your "vendors:” –CROs, clinical investigators, contract manufacturers, API makers –IRBs – they have been shut down in past –Joint venture partners – e.g., Cialis® – Lilly manufacturing plant problems – delayed about one year –Remember – even when you outsource, you are still ultimately responsible for what happens and you still need to have systems and people in place to ensure your vendors are working correctly Don't bury your head to problems -- investigate and disclose promptly

24 Tips to avoid problems & speed review… Don’t fall madly in love with your technology – understand that you have to prove safety and effectiveness – “I just know it works” is not the standard The process is very complex – this is a mere overview – build the right team to tackle –But, be careful with involving lobbyists, Congressmen/women, etc., at any stage

The Approval Gate Hopefully, will open for you!! But the odds are long, the cost is high, and the time is lengthy »Good luck!!

26 Call, , fax or write: Michael A. Swit, Esq. Vice President, Life Sciences THE WEINBERG GROUP INC. 336 North Coast Hwy. 101 Suite C Encinitas, CA Phone Fax Cell D.C. Office Questions?

27 About your speaker… Michael A. Swit, Esq., is Vice President, Life Sciences at THE WEINBERG GROUP, where he develops and ensures the execution of a broad array of regulatory and other services to clients, both directly and through outside counsel. His expertise includes FDA and CMS development strategies, compliance and enforcement initiatives, recalls and crisis management, submissions and related traditional FDA regulatory activities, labeling and advertising, and clinical research efforts for drug, biologic, device, IVD, and other life sciences companies, as well as those in the food and dietary supplement industries. Mr. Swit has been addressing critical FDA legal and regulatory issues since His vast and multi-faceted experience includes serving for three and a half years as corporate vice president, general counsel and secretary of Par Pharmaceutical, a prominent, publicly-traded, generic drug company and, thus, he brings an industry and commercial perspective to his work with FDA-regulated companies. Mr. Swit then served for over four years as CEO of FDANews.com, a premier publisher of FDA regulatory newsletters and other specialty information products for the FDA-regulated community. His private FDA regulatory law practice has included service as Special Counsel in the FDA Law Practice Group in the San Diego office of Heller Ehrman White & McAuliffe and with the Food & Drug Law practice at McKenna & Cuneo, both in the firm’s Washington office and later in San Diego. He first practiced FDA regulatory law with the D.C. office of Burditt & Radzius. Mr. Swit has taught and written on a wide variety of subjects relating to FDA law, regulation and related commercial activities, including, since 1989, co-directing a three-day intensive course on the generic drug approval process and editing a guide to the generic drug approval process, Getting Your Generic Drug Approved. A former member of the Food & Drug Law Journal Editorial Board, he also has been a prominent speaker at numerous conferences sponsored by such organizations as RAPS, FDLI, and DIA.

28 For more than twenty years, leading companies have depended on THE WEINBERG GROUP when their products are at risk. Our technical, scientific and regulatory experts deliver the crucial results that get products to market and keep them there.