Alternative Approaches to FDA Approval for Drug and Device Firms

Solving FDA Legal Challenges for the Life of a Life Sciences Company -1- www.fdacounsel.com
LAW OFFICES OF MICHAEL A. SWIT
Alternative Approaches to FDA Approval
for Drug and Device Firms
San Diego Regulatory Affairs Network
February 12, 2015
Michael A. Swit, Esq.

Standard Disclaimers
➢ Views expressed here are solely mine and do not
reflect those of my law 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.

➢ “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)
Early Efforts to Speed Drug Approval

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

➢ Accelerated Approval – very similar to Fast Track (see later 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
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

➢ 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”
Accelerated Drug/Biologic 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

➢ “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)
Accelerated – FDASIA Changes

➢"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
Fast Track Drugs

➢ 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
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
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 --
Fast Track …

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

➢ 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 demonstrate substantial 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 -- DG is silent on whether it meets that
duty under FDASIA
Breakthrough Therapies

➢ “Preliminary clinical evidence” – DG at 10.
– “could include” early evidence of both a clinical benefit and an
effect on a mechanistic biomarker – “usually from Phase 1 and 2
trials”
– should have a sufficient number of patients to be credible
– must show a substantial improvement over available therapy (AT)
– ideally is a controlled study vs. AT or placebo (if no AT)
– could be vs. historic control, but FDA will expect a large
difference in favor of the new drug
Breakthrough Therapies …

➢ “Substantial improvement” – DG at 11 -- subjective:
– depends on “magnitude of the treatment effect, which could
include duration of effect, and the importance of the observed
clinical outcome. But, should be a clear advantage over AT:
• a much greater or more important response
• treats the underlying cause as opposed to symptoms and preliminary
evidence show “significant efficacy”
• reversal of disease vs. symptomatic improvement
• important safety advantage
– DG contemplates that it could involve adding the new drug to
AT (but, DG is silent on how this jibes with FDA’s Combination
Drug policy at 21 CFR 300.50)

➢ “Clinically significant endpoints” – DG at 12 -- one
that measures an effect on:
– irreversible morbidity or mortality (IMM); or
– on symptoms that represent serious consequences of the disease
– or that suggest an impact on IMM or serious symptoms, such as:
• effect on an established surrogate endpoint
• effect on surrogate endpoint or intermediate clinical endpoint considered
reasonable likely to predict a clinical benefit (Acc. App.)
• effect on a pharmacodynamic biomarker that strongly suggests potential
for a clinically meaningful effect on the disease
• significantly improved safety profile

➢ All Fast Track benefits
➢ Intensive guidance from FDA on Efficient Drug
Development as Early as Phase 1
– sponsor should be ready “for a more rapid pace”
➢ Organizational commitment of senior managers
– “proactive, collaborative, cross-disciplinary review”
– cross-disciplinary project lead – to coordinate among all parts of
FDA review team (CMC, clinical, pharm-tox, etc.)
➢ FDA may even ask you to seek Breakthrough status
➢ Designation process – covered by Appendix 1 to DG
Breakthrough Therapies … Benefits

➢ Early indications – agency might allow some
breakthrough therapies to get to market on the basis of a
single Phase 1 study – Janet Woodcock – Bloomberg
interview
➢ Vertex – already has two “breakthrough” designations –
for two CF drugs

➢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)
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
FDA Review Priority System

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)

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/C
entersOffices/OfficeofMedicalProductsand
Tobacco/CDER/ManualofPoliciesProced
ures/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/GuidanceComplianceRegul
atoryInformation/ProceduresSOPP
s/ucm073481.htm

➢ “Serious condition” –
– a disease or condition associated with morbidity that has
substantial impact on day-to-day functioning. Short-lived and
self-limiting morbidity will usually not be sufficient, but the
morbidity need not be irreversible if it is persistent or recurrent.
Whether a disease or condition is serious is a matter of clinical
judgment, based on its impact on such factors as survival, day-to-
day functioning, or the likelihood that the disease, if left
untreated, will progress from a less severe condition to a more
serious one.” DG @ 2.
Key Concepts from the Draft Guidance

Key Concepts from the Draft Guidance …
➢ Does the drug treat the serious condition?
– must have an effect on a serious aspect of the serious condition,
but this could include:
– product intended to treat or improve a serious treatment-related
side effect (e.g., serious infections in patients receiving
immunosuppressive therapy)
– product intended to avoid a serious adverse effect associated with
the available therapy (e.g., less cardiotoxicity than an available
cancer therapy)

➢ “Available Therapy” or “Existing Therapy” or
“Existing Treatment” – is one that:
– is approved or licensed in the U.S. for the same indication being
considered for the new drug; and
– is relevant to the current U.S. standard of care (SOC) for the
indication
• can be a non-drug therapy
• in rare cases, can be unapproved if safety and effectiveness is supported
by “compelling evidence” – DG @ 3
• determined as of relevant time for the specific expedited program
• Available Therapy guidance -- July 2004 will be replaced by the DG when
finalized

➢ “Unmet medical need” – a condition that is not met
adequately by available therapy (“AT”)
– Can reflect two types of need:
• specific to the patient population (most common)
• addresses a societal need – e.g., antibiotic resistance
– –Ways differs from AT to constitute serving an “unmet” need
• impacts a serious outcome of a condition not yet served
• improved effectiveness on serious outcome vs. AT
• works for patients unresponsive to AT or who can’t tolerate AT
• similar efficacy to AT, but less side effects
• similar safety and efficacy, but another benefit such as greater compliance;
leads to improved outcomes

➢ 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
The 505(b)(2) NDA

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

Alternative Approaches for Devices

The Not-so “New 510(k) Paradigm”
➢ Part of CDRH Reengineering in mid-90’s
➢ Sources:
– Guidance – March 1998 –
– FAQ – October 1998

The “Special 510(k)”
➢ 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

Special 510(k) …
➢ 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

Special 510(k) …
➢ 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

The “Abbreviated” 510(k)
➢ 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

Expedited Access for PMA Devices
➢ For Unmet Medical Need for Life Threatening or
Irreversibly Debilitating Diseases or Conditions
– Draft Guidance – April 2014
– “Expedited Access PMA” or “EAP”
➢ Core Aspects -- Integrated communications during
device development and IDE and PMA review
– “Data Development Plan” – aimed at creating all data – and
timelines for collecting/generating them -- needed for premarket
and post-market support of device approval
– Implements the power FDA has under Act to use postmarket
controls to balance need for premarket data in approving a PMA

➢ Sponsor must request an EAP and FDA must agree
➢ EAP – for a Life Threatening or Irreversibly
Debilitating Disease or Condition (LITDDC)
– Potential for “clinically meaningful benefit” over AT; or
– A “breakthrough” technology over current device therapy
➢ Potential benefits of EAP
– Use of surrogate endpoints
– Less detailed manufacturing info for PMA
– Inspections may be deferred to post-approval
– Ability to defer certain data collection to post-market stage
EAP …

➢ Four stages of EAP
– Designation request
– Agreement with FDA on a Device Development Plan (DDP)
– PMA Review
– Post-market Data requirements
➢ “Life Threatening” –
– Likelihood of death is high unless disease progress is interrupted
– Examples: chronic or active hepatitis; myocardial infarction
EAP …

➢ “Irreversibly Debilitating”
– Condition or disease that has a substantial impact on day-to-day
functioning
➢ Unmet Need
– “Breakthrough” – potential to provide a “clinically meaningful
advantage over existing technology”; or
– No alternative means to treat or diagnose exists
➢ Review Advantages
– Interactive
– Dedicated senior CDRH management, plus a “case manager”
– Priority review
EAP …

Reclassification
➢ Traditional Reclassification Petition – Section 513(e)
– Slower – 180 days as with any other Citizen Petition
➢ de Novo 510(k) – 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
– Draft Guidance – August 2014 – replaced an October 2011 guidance
that was very detailed and demanding – 2014 draft appears more
reasonable.

Questions?
➢ Call, e-mail or write:
Michael A. Swit, Esq.
San Diego, California 92130
m: 760-815-4762
e: mswit@fdacounsel.com
web: www.fdacounsel.com
➢ Follow me on:
– LinkedIn: http://www.linkedin.com/in/michaelswit
– Twitter: https://twitter.com/FDACounsel

About Your Speaker
Michael A. Swit, Esq., has been addressing critical FDA legal and regulatory issues for over 30
years. Before returning to his private law practice in late 2017, he served for 3 years as the chief
regulatory counsel at a leading developer of diagnostics and research tools. Prior to that, Swit was a
special counsel in the FDA Law Practice at the global law firm of Duane Morris LLP, in its San
Diego office. 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, therapeutic biotech products, medical devices, and IVDs.
His FDA legal and regulatory work also has included tenures 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, where he helped spearhead the
company’s emergence from the Generic Drug Scandal. 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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