Sdran --alternative_approaches_to_approval_--_nov._2006--_handout_version

San Diego Regulatory Affairs Network
November 28, 2006
Alternative Approaches to FDA
Approval for Drug and Device Firms
Michael A. Swit
Vice President

2
Early Efforts to Speed Drug Approval
• “Subpart E” Regulations – 53 Fed. Reg. 41516
(October 21, 1988) -- http://www.fda.gov/Cber/gdlns/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)

3
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

4
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

5
• 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

6
• 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

7
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

8
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

9
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

10
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 -- http://www.fda.gov/cber/gdlns/pdufa1.pdf
• Scientific Feedback – 10/03 -- http://www.fda.gov/cber/gdlns/pdufa2.pdf

11
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

12
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)

13
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

14
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” @
http://www.fda.gov/cber/gdlns/availther.pdf
• Accelerated Approval drugs do not necessarily
get Priority Review – contrast “meaningful”
(AA) vs. “significant” improvements (PR)

15
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/cder/mapp/602
0-3.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 @
http://www.fda.gov/cber/regsopp/8
405.htm

16
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

17
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

18
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

19
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
aren’t 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?

20
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 @ www.fda.gov/cber/regsopp/8413.htm

21
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

22
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

23
Alternative Approaches for Devices

24
The “New 510k Paradigm”
• Part of CDRH Reengineering in mid-90’s
• Sources:
– Guidance – March 1998 --
http://www.fda.gov/cdrh/ode/parad510.pdf
– FAQ – October 1998 --
http://www.fda.gov/cdrh/ode/qanda510k.pdf

25
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” @ 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

26
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

27
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

28
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

30
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

31
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

32
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]

33
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
• Device firm can not charge more than R&D,
fabrication and distribution costs
• HUDs can only be used
– In facilities with IRBs
– And with prior IRB approval, unless emergency use OK’d by
a doctor based on lack of timely IRB review

34
HDEs …
• Sources of info:
– Regulations – 21 CFR 814.100 – 814.126
– Q&A Guidance – July 2006
http://www.fda.gov/cdrh/ode/guidance/1381.pdf
– HDE Checklist for Filing Decisions --
http://www.fda.gov/cdrh/ode/checklst.pdf
– List of HUD’s Approved by FDA –
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfHDE/HDEInf
ormation.cfm

35
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 760.633.3343
Fax 760.633.3501
Cell 760.815.4762
D.C. Office 202.730.4123
michael.swit@weinberggroup.com
www.weinberggroup.com
Questions?

36
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 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.

37
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.
Washington, D.C. ♦ San Francisco ♦ Brussels ♦ Edinburgh

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