Webinar sponsored by Compliance2Go focusing on different ways that drug and medical device firms can secure approval of products outside of traditional approaches. Presentation covers: * accelerated approval * breakthrough therapies * fast track drugs * priority review

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Alternative Approaches to FDA Approval for
Drug and Device Firms
A Compliance2go Seminar
February 21, 2013
Michael A. Swit, Esq.

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Standard Disclaimers
• Views expressed here are solely mine and do not
reflect those of my firm or any of its clients.
• This presentation supports an oral briefing and
should not be relied upon solely on its own to
support any conclusion of law or fact.
• These slides are intended to provide general
educational information and are not intended to
convey legal advice.
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Early Efforts to Speed Drug Approval
• “Subpart E” Regulations – 53 Fed. Reg. 41516
(October 21, 1988) --
– 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 (see late
slides), but developed by regulation before FDAMA – 21
CFR 314.500-560 – “Subpart H”
– promulgated at 57 Fed. Reg. 58942 (Dec. 11, 1992)
• 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 Drug/Biologic Approval …
• Evidence to support that a drug has the effect
required (see prior slide) – may come from:
– epidemiological, pathophysiological, therapeutic,
pharmacologic, or other evidence developed using biomarkers,
for example, or other scientific methods or tools.”
§506(c)(1)(B)
• Still have to do post-approval studies –
– but, those studies no longer have to validate a surrogate
endpoint or confirm effect on the clinical endpoint
– rather, “verify and describe the predicted effect on the
irreversible morbidity or mortality or other clinical benefit”
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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 drug’s 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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Accelerated – FDASIA Changes
• “Serious or life-threatening disease or condition”
• Fast track = accelerated situation with an unmet
need
• Based on:
– determination that the product has an effect on a surrogate
endpoint that is reasonably likely to predict clinical benefit, or
on a clinical endpoint that can be measured earlier than
irreversible morbidity or mortality, that is reasonably likely to
predict an effect on irreversible morbidity or mortality or other
clinical benefit, taking into account the severity, rarity, or
prevalence of the condition and the availability or lack of
alternative treatments.” § 506(c)(1)(A)
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Accelerated -- FDASIA Changes …
• Evidence to support that a drug has the effect
required (see prior slide) – may come from:
– epidemiological, pathophysiological, therapeutic,
pharmacologic, or other evidence developed using biomarkers,
for example, or other scientific methods or tools.”
§506(c)(1)(B)
• Still have to do post-approval studies –
– but, those studies no longer have to validate a surrogate
endpoint or confirm effect on the clinical endpoint
– rather, “verify and describe the predicted effect on the
irreversible morbidity or mortality or other clinical benefit”
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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 3]
 “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 FDA’s 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 FDA’s rolling review
process
 Reviewable Units – 10/03 –
 Scientific Feedback – 10/03 --
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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
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Breakthrough Therapies
• FDA may accelerate approvals -- § 506(a)(1)
• Defined as a drug intended to treat, alone or in
combination:
– a serious or life-threatening disease or condition and preliminary clinical
evidence indicates that the drug may demonstratesubstantial improvement
over existing therapies on one or more clinically significant endpoints, such
as substantial treatment effects observed early in clinical development
• Designation – any time at or after submitting IND
– FDA – 60 days to decide if a breakthrough therapy
– If designated, FDA must act to “expedite development and review of the
application” via such measures as meetings and development advice
– Guidance – no later than January 2014
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Breakthrough Therapies …
• Early indications – agency might allow some
breakthrough therapies to get to market on the basis of a
single study – Janet Woodcock – Bloomberg interview
• Vertex – already has two “breakthrough” designations –
for two CF drugs
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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”
• 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 @
http://www.fda.gov/downloads/AboutFDA
/CentersOffices/OfficeofMedicalProd
uctsandTobacco/CDER/ManualofPol
iciesProcedures/ucm082000.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 @
http://www.fda.gov/BiologicsBloodVa
ccines/GuidanceComplianceRegu
latoryInformation/ProceduresSOP
Ps/ucm073481.htm

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Antibiotics – G.A.I.N.
• Generating Antibiotic Incentives Now (G.A.I.N.) –
new § 505E of the Act
– “Qualified Infectious Disease Product” (QIDP) – adds five
years to existing Waxman-Hatch exclusivity (including
extending, for NCE, period during which ANDA can’t be
filed, from 4 to 9 years)
– QIDP – “an antibacterial or antifungal drug for human use
intended to treat serious or life-threatening infections,
including those caused by …”
 an antibacterial or antifungal resistant pathogen; or
 certain “qualifying pathogens”
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Antibiotics – G.A.I.N. …
• “Qualifying Pathogens” – to be included in a list to be
maintained by FDA – includes those pathogens that:
– have potential to pose a serious risk to public health (e.g.,
resistant gram positive; multi-drug resistant gram negative
bacteria; multi-drug resistant TB; and Clostridium difficile)
– list to be made not later than July 9, 2014
• QIDP Designation – may be requested any time before
submitting an NDA
– FDA must decide within 60 days
• Implementing regulations – due by July 9, 2014
• Priority Review – post-FDASIA QIDP NDAs – get
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FDA Flexibility on Data Requirements
• FDAMA § 115(a) -- data from one adequate and well-
controlled study and confirmatory 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
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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)
• Post-FDAAA – now can be required as part of a REMS
program
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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 under Waxman-Hatch
• 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 Not-so “New 510k Paradigm”
• Part of CDRH Reengineering in mid-90’s
• Sources:
– Guidance – March 1998 –
– FAQ – October 1998
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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” – 1997 (not the Dec. 2011 guidance,which was revoked
by FDASIA)
– 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 fundamentalscientific 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, performancespecs, ergonomics of
patient-user interface, dimensionalspecs, 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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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
– Old Fiction – have to submit the 510k and then get it denied as
NSE; then request reclassification – eliminated by FDASIA
– 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 – October 2011 – very detailed and demanding
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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 < 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 …
• FDA’s 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
• Charging:
– Originally -- device firm can not charge more than R&D,
fabrication and distribution costs
– FDASIA change -- Humanitarian Device Exemption (HDE) –
now can make a limited profit. Previously, only pediatric
devices qualified -- §520(m)(6)(A)
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Questions?
• Call, e-mail or fax:
Michael A. Swit, Esq.
Special Counsel, FDA Law Practice
Duane Morris LLP
San Diego, California
direct: 619-744-2215
fax: 619-923-6248
maswit@duanemorris.com
• Follow me on:
– LinkedIn: http://www.linkedin.com/in/michaelswit
– Twitter: https://twitter.com/FDACounsel
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About Your Speaker
Michael A. Swit, Esq., is a Special Counsel in the San Diego office of the international law firm,
Duane Morris, LLP, where he focuses his practice on solving FDA legal challenges faced by
highly-regulated pharmaceutical and medical device companies. Before joining Duane Morris in
March 2012, Swit served for seven years as a vice president at The Weinberg Group Inc., a
preeminent scientific and regulatory consulting firm in the Life Sciences. His expertise includes
product development, compliance and enforcement, recalls and crisis management, submissions
and related traditional FDA regulatory activities, labeling and advertising, and clinical research
efforts for all types of life sciences companies, with a particular emphasis on drugs, biologics and
therapeutic biotech products. Mr. Swit has been addressing vital FDA legal and regulatory issues
since 1984, both in private practice with McKenna & Cuneo and Heller Ehrman, and as vice
president, general counsel and secretary of Par Pharmaceutical, a top public generic and specialty
drug firm. He also was, from 1994 to 1998, CEO of FDANews.com, a premier publisher of
regulatory newsletters and other specialty information products for FDA-regulated firms. He has
taught and written on many topics relating to FDA regulation and associated commercial
activities and is a past member of the Food & Drug Law Journal Editorial Board. He earned his
A.B., magna cum laude, with high honors in history, at Bowdoin College, and his law degree at
Emory University.
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