San Diego Regulatory Affairs Network

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Alternative Approaches to FDA Approval for Drug
and Device Firms

• San Diego Regulatory Affairs Network
• November 28, 2006

Michael A. Swit Vice President
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Early Efforts to Speed Drug Approval

• Subpart E Regulations 53 Fed. Reg. 41516
  (October 21, 1988) -- http//www.fda.gov/Cber/gdln
  s/fsttrk-2.pdf
• IND rules Procedures for Drugs Intended to
  Treat Life Threatening and Severely Debilitating
  Illnesses codified at 21 CFR 312.80 - 312.88
• Basics
• life threatening 21 CFR 312.81(a)
• likelihood of death is high unless disease course
  is interrupted and
• Diseases with potentially fatal outcomes where
  the endpoint of clinical trial analysis is
  survival
• severely debilitating diseases that cause
  major irreversible morbidity 21 CFR 312.81(b)

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Subpart E

• Provisions to Speed Development
• Early consultation 312.82 to review and
  reach agreement on preclinical and clinical
  studies
• Pre-IND meetings
• End of Phase 1 Meetings -- to try to ensure that
  Phase 2 studies are sufficient to support
  approval
• Meeting Process per 312.47(b)(1) for EOP2
  meetings
• Treatment Protocols 312.83 FDA can ask for if
  Phase 2 data appear promising
• Risk-Benefit Analysis in Review of Applications
  312.84
• Phase 4 Studies 312.85

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Accelerated Approval

• Accelerated Approval very similar to Fast
  Track, but developed by regulation before FDAMA
  21 CFR 314.500-560
• promulgated at 57 Fed. Reg. 58942 (Dec. 11, 1992)
• http//www.fda.gov/Cber/gdlns/fsttrk-4.pdf
• Eligible Drugs -- must
• treat serious or life-threatening illnesses
• provide meaningful therapeutic benefit to
  patients over existing treatments
• 21 CFR 314.500
• Approval can be based on
• a surrogate endpoint that is reasonably likely
  based on epidemiologic, therapeutic,
  pathophysiologic or other evidence to predict
  clinical benefit or
• on the basis of an effect on a clinical endpoint
  other than survival or irreversible morbidity
• 21 CFR 314.510

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Accelerated Approval

• Surrogate Marker a laboratory measurement, sign
  or symptom, that if changed by a therapy, would
  not, in and of itself, be clinically significant
  enough as a basis to evaluate therapeutic success
• Surrogate Endpoint is a pre-defined change in a
  surrogate marker that is a primary or secondary
  outcome of a treatment trial

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Accelerated Approval

• To assure safety, FDA can restrict distribution
  or impose other post-marketing restrictions, such
  as
• Distribution limited to certain facilities or
  types of physicians
• Contingent on certain testing
• 21 CFR 314.520
• Promotional materials subject to prior review,
  both before and after approval
• 21 CFR 314.550
• Phase 4 Studies commonly required to verify and
  describe the drugs clinical benefit
• Still exists after FDAMA, but Fast Track may have
  more flexibility as to eligibility
• e.g., -- even if a drug is approved under
  Accelerated Approval for a condition, another
  drug to address that is possible under Fast Track
  

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Fast Track Drugs

• "Fast Track" -- FDAMA 112 created new Section
  506 of the Federal Food, Drug, and Cosmetic Act
  (the Act) essentially codifies Accelerated
  Approval
• Eligibility
• Treats a "serious or life threatening condition
• life threatening same as under Subpart E 21
  CFR 312.81(a) see SLIDE 2
• serious
• Life threatening
• Associated with a morbidity that has substantial
  impact on day-to-day functioning treats a
  serious aspect of that disease
• To illustrate -- if drug treats alopecia due to
  Lupus, the indication is not serious, even though
  Lupus is thus drug is not fast track

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Fast Track

• Eligibility
• Shows "potential to address unmet medical needs
  for such condition
• Condition not addressed adequately by an existing
  therapy
• Can be non-drug therapy
• Unmet medical need not limited to efficacy, can
  also be an improvement in safety or side effects
• Note if only other approval is under
  Accelerated Approval rules, then it is still
  unmet due to potential Phase 4 Studies of
  previously-approved drug will undermine the
  approval of that drug
• Have to request designation as Fast Track in
  writing at time of filing IND or after (but
  before NDA/BLA approval)
• If eligible, FDA must "facilitate the development
  and expedite and review" of the drug using
  mechanisms similar to with AA
• Pre-IND, EOP1, EOP2, and pre-NDA/BLA meetings

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Fast Track

• Approval as with Accelerated -- can be made on
  the basis of clinical or surrogate endpoints or
  under normal approval standards (thus avoiding
  Phase 4 studies, commonly)
• Rolling NDA/BLA -- may be eligible to submit
• At FDAs discretion
• Clinicals must be near completion or done
• FDA agrees drug continues to meet eligibility
  criteria
• FDA agrees preliminary evaluation of data
  supports a determination that the drug may be
  effective

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Fast Track

• Rolling NDA/BLA
• Must provide FDA with a schedule for submitting
  all sections and FDA must agree to the schedule
  done at pre-NDA/BLA meeting
• Usually, must be complete sections
• Must pay user fees at time of first submission,
  but review clock does not start until full
  NDA/BLA submitted
• Guidances issued for Pilot programs on rolling
  submissions provide additional insight on FDAs
  rolling review process
• Reviewable Units 10/03 -- http//www.fda.gov/cbe
  r/gdlns/pdufa1.pdf
• Scientific Feedback 10/03 -- http//www.fda.gov/
  cber/gdlns/pdufa2.pdf

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Fast Track

• Can lose status along way
• Clinical study data fail to establish benefit
• New approvals of other products change the unmet
  need situation
• Promotional Materials also subject to prior
  review
• Section 113 of FDAMA requires you to submit
  information on FT and AA effectiveness clinical
  studies to www.clinicaltrials.gov
• For more info, see 2006 Guidance on Fast Track
• http//www.fda.gov/cber/gdlns/fsttrk.pdf

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FDA Review Priority System

• 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)

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FDA Review Priority System

• 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 -- 10 month PDUFA clock
• P - Priority significant advances over
  existing treatments (including non-drug) 6
  month PDUFA clock

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Review Priority

• Can lose Priority status if circumstances change,
  but not during first review cycle (per CDER)
• Key reason -- available therapies change so as to
  undermine prior conclusion that your drug creates
  a significant improvement -- see FDA Guidance on
  Available Therapy _at_
• http//www.fda.gov/cber/gdlns/availther.pdf
• Accelerated Approval drugs do not necessarily get
  Priority Review contrast meaningful (AA) vs.
  significant improvements (PR)

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CDER vs. CBER on Priority Eligibility

• CDER
• Significant improvement compared to marketed
  products (including non-drugs) in the treatment,
  diagnosis, or prevention of a disease
• Does not have to be life threatening
• see CDER MaPP 6020.3 _at_
• http//www.fda.gov/cder/mapp/6020-3.pdf

• CBER
• Significant improvement in the safety or
  effectiveness of the treatment, diagnosis or
  prevention of a
• Serious or life threatening disease
• see CBER SOPP 8405 _at_
• http//www.fda.gov/cber/regsopp/8405.htm

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FDA Flexibility on Data Requirements

• FDAMA 115(a) -- data from one adequate and
  well-controlled study and confiirmatory evidence
  can be used to show substantial evidence of
  effectiveness
• "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

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How to Nail Down What FDA Wants

• 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 (SPA) FDA
  process for implementing

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Is an SPA Always the Answer?

• Advantages
• Binding on FDA (unless subsequent safety or
  effectiveness issue arises)
• Increases predictability
• Investment community likes
• Must be in writing
• 45 Days for FDA to address can be faster to get
  to a meeting than some other types of agency
  meetings

• Disadvantages
• Process can be iterative too long going to
  fro to get final agreement
• Binding on you as well what happens if you find
  out something that would make you want to change
  the trial design?
• Less flexibility later on if need to massage
  the data a little

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Phase 4 Commitments

• The statistical record subject to great
  criticism and inherent problems
• ODAC 2003 review
• Eight AA cancer drugs were projected to need 10
  years to complete Phase 4 studies
• Recruitment is difficult
• Congressional scrutiny in wake of Vioxx, et al.
  the studies arent getting done promptly at
  the time of 2002 FDA Report under FDAMA on PMC,
  only 882 out of 2400 drug PMCs were completed
• The challenge do you want to go on the market
  with a key parameter unproven and risk a market
  withdrawal?

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Phase 4 Studies

• Duties while studies ongoing Post-Marketing
  Commitments (PMC) file periodic reports see
  21 CFR 314.81 (for drugs) or 21 CFR 601.70 (for
  biologics)
• Guidance Reports on the Status of Postmarketing
  Study Commitments February 2006
• http//www.fda.gov/cber/gdlns/post130.pdf
• CBER SOPP 8413 _at_ www.fda.gov/cber/regsopp/8413.h
  tm

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The 505(b)(2) NDA

• An application where the applicant does not have
  a right of reference to data being relied upon
  erroneously referred to by some as a Paper NDA
• Examples of such data
• FDA prior conclusions in an NDA
• Published literature
• Almost a full NDA
• Requires a patent certification
• Can get Exclusivity
• Handle like a full NDA pre-IND to IND to NDA

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The ANDA Suitability Petition

• Creates an exception to the general rule under
  Waxman-Hatch that you need a reference listed
  drug to support an ANDA
• Examples
• Dosage form -- tablet to capsule change
• Strength usually lower or intermediate if
  consistent with labeled dosing regimen higher
  rare
• Route of administration possible, but rarer
• PPA Patch -- denied
• Ingredient only a single ingredient in a
  combination drug
• Different salts not allowed
• Advantage product line extension
• Disadvantage no exclusivity anyone else can do
  same thing timing is important

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Alternative Approaches for Devices
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The New 510k Paradigm

• Part of CDRH Reengineering in mid-90s
• Sources
• Guidance March 1998 --http//www.fda.gov/cdrh/od
  e/parad510.pdf
• FAQ October 1998 -- http//www.fda.gov/cdrh/ode/
  qanda510k.pdf

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The Special 510k

• Modification to already-cleared device
• If change could significantly impact safety or
  effectiveness, needs a new 510k
• see also Deciding When to Submit a 510(k) for a
  Change to an Existing Device _at_
  http//www.fda.gov/cdrh/ode/510kmod.pdf
• Subject to design controls as of 1997
• If new 510k needed for a change and the
  modification does NOT affect
• the intended use of the device, or
• alter its fundamental scientific technology
• Can use summary info generated under design
  controls to support the 510k

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Special 510k

• Must do verification and validation to determine
  that design outputs meet design inputs
• Filing contains a Declaration of Conformity
  with design controls for the change
• Processed within 30 days of receipt by CDRH
• Ineligible changes
• Changes to indications of use
• Changes to labeling that impact intended use

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Special 510k

• Ineligible changes
• Changes to fundamental scientific technology
• Operating principles
• Mechanism of action
• e.g., automation of a manual device
• Changes in materials
• In an implant or device that contacts the body or
  fluids where the material has not been so used
  before
• Examples of eligible changes
• Energy type, environmental specs, performance
  specs, ergonomics of patient-user interface,
  dimensional specs, software or firmware,
  packaging or expiration dating, sterilization
• General Rule if need clinical studies, unlikely
  to get Special 510k

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The Abbreviated 510k

• May be used if any of the following cover the
  device
• FDA guidance document
• Special Controls per Section 513(a)(1)(B) of the
  Act
• An FDA-recognized consensus standard
• For an FDA guidance or special controls, submit
  a summary report saying how you met the guidance
  or controls during device development and testing
• For consensus standards, do same (as in previous
  bullet), but also include a declaration of
  conformity to the standard

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The Paradigm in Action
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Reclassification

• Traditional Reclassification Petition Section
  513(e)
• Slower 180 days as with any other Citizen
  Petition
• de Novo 510k for new technology Section
  513(f)(2) of Act result of FDAMA
• Fiction have to submit the 510k and then get it
  denied as NSE then request reclassification
• Must give grounds for down classification
• In reclassification request, you can recommend
  the new class and any applicable controls
• Faster FDA has 60 days
• Guidance -- http//www.fda.gov/cdrh/modact/clasiii
  .pdf

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Humanitarian Device Exemptions (HDE)

• Created in 1990 by Safe Medical Devices Act
  (SMDA)
• Humanitarian Use Device (HUD) per 21 CFR
  814.3(n) device intended to benefit patients
  in the treatment of a disease or condition that
  affects or is manifested in fewer than 4,000
  individuals in the United States per year
• HDE a PMA seeking a humanitarian device
  exemption from the effectiveness requirements of
  sections 514 and 515 of the Act per Section
  520(m)(2) of the Act

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HDEs

• Qualifying under SMDA
• Device treats or diagnoses a condition lt 4,000
• Device would not be available but for an HDE and
  there is no available comparable device
• Device will
• not expose patients to an unreasonable or
  significant risk of illness or injury, and
• Probable benefit to health by using device
  outweighs risk, taking into account the probable
  risks and benefits of currently available
  treatments device or otherwise

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HDEs

• FDAs Office of Orphan Products must designate
  the device as a HUD before submitting the HDE to
  CDRH per 21 CFR 814.102
• FDA has 75 days to approve the request
• Device firm can not charge more than RD,
  fabrication and distribution costs
• HUDs can only be used
• In facilities with IRBs
• And with prior IRB approval, unless emergency use
  OKd by a doctor based on lack of timely IRB
  review

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HDEs

• Sources of info
• Regulations 21 CFR 814.100 814.126
• QA Guidance July 2006 http//www.fda.gov/cdrh/o
  de/guidance/1381.pdf
• HDE Checklist for Filing Decisions --
  http//www.fda.gov/cdrh/ode/checklst.pdf
• List of HUDs Approved by FDA
  http//www.accessdata.fda.gov/scripts/cdrh/cfdocs/
  cfHDE/HDEInformation.cfm

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Questions?
Call, e-mail, fax or write Michael A. Swit,
Esq. Vice President THE WEINBERG GROUP INC. 336
North Coast Hwy. 101 Suite C Encinitas, CA
92024 Phone [phone] Fax
760.633.3501 Cell 760.815.4762 D.C. Office
202.730.4123 michael.swit_at_weinberggroup.com www.we
inberggroup.com
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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 1984. 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 firms 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.
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