Transcript Slide 1

Michael A. Swit, Esq.
Vice President
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Ensuring FDA Regulatory Success for Biomedical
Companies
Merage Foundation
Israel Life Sciences Fellows Program
Irvine, California
February 27, 2008
Standard Disclaimers
 Views expressed here are solely my own and do not
necessarily reflect those of my firm or any of our clients.
 These slides support an oral briefing and may not be relied
upon solely on their own to support any conclusion of law
or fact.
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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
Where The Pitfalls Lie
 Overall Planning
 Working With FDA
 Clinical Trial Execution
 CMC and Design History Issues
 Safety Issues
 Labeling
 Ingredients – Active And Inactive; Component for Medical
Devices
 Final Sermons
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Overall Planning

Create A Project Plan With Well-defined Go/No-go
Decision Points –
 Difficult, But Vital To Know When To Shift Gears.
 Plan With The End In Mind – your ultimate labeling will
drive what you need to do – create a “Product Profile” early
and try to stick to it.
 Clinical Regulatory Integrated Strategic Plan (CRISP)
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Overall Planning …
 Understand What Your Product Is:
 Drug
 Biologic (but regulated as a drug in U.S.)
 Device
 Combination Product
 Cosmetic
 Dietary Supplement
 Food
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Overall Planning …

Make Sure You Are Ready To Go From “R" to “D"
 Internally - people and systems; change in mindset from research to
development.
 Formulation or Design -- Rigorously Reviewed -- so as to optimize
your chances when going into humans.
 Once Clinical Evaluation With A Compound or Prototype Begins,
Preclinical Efficacy Experiments -- should be limited or undergo
rigorous review and oversight.
 Educate Scientists And Researchers – on the realities of the demands
of development, especially documentation
 Example -- report writing -- may be a weakness in research, but is
important in development. Start early in the process.
 Design Controls SOPs – when they apply; what to do before hand
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Overall Planning …

Make Sure Regulatory, Clinical, And Sales & Marketing Are All
Talking Early On –
 Ensure Indication or Intended Use (thus, Endpoints) Being Studied
Is One You Want To Sell
 Some Considerations
 Study Design –while marketing may want superiority if you go for that
sort of study and fail, the FDA won’t let you reanalyze the study for noninferiority -- hence failed development program…
 Indication or Intended Use Choice – consider limited initial indication
that can be the starting point for subsequent bigger indications
 can be key to optimal product lifecycle management
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Overall Planning …

Beware of "Divergent Evolution" between Product Development
and Intellectual Property Efforts!
 How Patents Can Evolve
 Attaining patent protection for a novel chemical entity or formulation – or
a device design -- is a multiyear process,
 In process, claims often become more limited in number and in scope, due
to prior art, Patent Examiner concerns, etc
 Ensure A Strategic Linkage Between The Product Development
And Patenting Efforts -- to best assure:
 Patent(s) granted actually cover critical features of the product being
studied in clinicals
 Clinicals actually cover patented/able claims
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Overall Planning …

Understand Approval Is Not Enough, Somebody Has
to Pay for It!! - coverage (on formulary) and reimbursement
(at a reasonable copay tier).
 Some keys:
 Label claims -- Is there anything novel you can say?
 Comparative effectiveness:
 future of reimbursement
 future for competitive/comparative claims
will be needed (FDA/FTC)
– clinicals
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Overall Planning …

Other Key Planning Efforts
 Product Name –
 Globalize the product name (be careful with different meanings)
 Seek regulatory agency concurrence early.
 Find Collateral Support; e.g., Patient Groups, Thought Leaders (aka
“Key Opinion Leaders” or “KOLs”)
 can help with identifying investigators
 can help with patient recruitment
 Identify Enemies -- commercial and otherwise (e.g., special interest
groups)
 Anticipate their moves (e.g., Citizen Petitions)
 Pediatric Assessments -- -need a plan to address pediatric usage for
drugs; may emerge for devices
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Overall Planning …

Management
 Must Understand Process.
 Must Support Company's Quality System, Especially As A Company
Matures.
 Device companies – affirmative duty under QSR regulations
 Don’t Let Financial Milestones Drive Development – recipe for
disaster (e.g., Refuse To Files, Clinical Holds).
 Contrast:
“What is the minimum we need to do to get approval?"
vs.
"What is necessary for us to provide in order to get a first cycle review
approval".
[if your CEO thinks first option is OK, time to update your CV]
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Coordinating with the EU
 Start planning early for simultaneous efforts
 Drug approvals – systems are somewhat similar, but not identical
 Complex considerations on scientific advice
 Need to ensure you understand if must co via Centralized Procedure or
can go Mutual or Individual Member states
 Devices – CE Marking Process is quite different from FDA
 Generally seen as less onerous than U.S.
 But, choose your Notified Body with care
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Working With FDA

Early interaction -- essential to understanding your path
and what you need for the journey
 FDA encourages and appreciates (usually) being consulted
early in the development stage -- helps build a relationship
with Agency that can pay off during the approval process.
 Take advantage of all Regulatory “value-added”
initiatives – e.g., Fast Track, Accelerated Approval, Orphan
Drug, SPA (but be careful on this)
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Working With FDA …

Seek to Ensure You Get Agency Agreement On Exactly What Is The
Indication – will drive related labeling language, especially if related to
disease, treatment or metrics
 Example: “Chronic sinusitis”
 Not in DSM or accepted text books -- really a term of art among ENTs.
 Company
 started clinical trials,
 Then, went to FDA – “we’re treating chronic sinusitis!!”
 FDA -- “what’s’ that?” -- leading to a rather lengthy debate about
symptomatology of “chronic sinusitis”.
 Result – company had already studied something not entirely covered by the now
agreed upon definition of “chronic sinusitis” both as to:
 outcomes
 method of measuring

Consequence – also can end up proving a labeled indication that does not jibe
with original marketing projections
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Working With FDA …

Safety is Lynchpin Today –
 Focus On Signals/AE’s Early
 Ensure personnel evaluating are qualified
 “REMS” –
 “Risk Evaluation and Mitigation Strategies”
 Future is now – due to Food & Drug Administration Amendments Act of
2007 –
 You Need to control REMS process; don’t let FDA

Example: anticipate Phase IV, Post-Approval Study, but drive its design
 Device approvals –consider similar risk management issues
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Working With FDA …

Logistics:
 Understand IND and IDE Regulations – especially on changes:
 Amendments
 Annual reports
 Use the Pre-IND and Pre-IDE processes – and later meetings such as
End of Phase 2 and pre-submission filing meetings -- educates FDA and
gain clarity on requirements
 Keep Detailed Records Of All Interactions between the sponsor and
the regulatory agencies.
 After Submission -- Be Very Diligent with Follow-Up.
 Ensure mandatory review milestones are achieved by the reviewer.
 “Force” dialogue if necessary.
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Working With FDA …

Logistics …
 Respond To FDA Deficiency Letters and Other Comments 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
 In responding to a deficiency letter:
 Respond to FDA's comment in the first sentence.
 Give clear and concise responses -- do not ramble and do not discuss other
topics.
 In a interacting with an FDA official, if you do not know the answer to a
query, do not guess.
 Refer to a colleague who could provide the response. or tell reviewer you will get
back with correct reply
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Working With FDA …

Formal Meetings
 Don’t Guess Who’s Coming to Dinner - FDA: learn as much as possible about the regulatory agency meeting
attendees – background (full CVs, hot buttons, past publications)
 Company: carefully pick who you will be taking to the meetings to represent
your company – internal people, consultants
 Rehearse, Rehearse, Rehearse: a well-rehearsed meeting = productive
meeting
 Anticipate questions -- have a plan of how and who will respond
 Use outsiders to prepare – otherwise, you lose perspective
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Working With FDA …

Formal Meetings
 Consider technology assistance -- for advisory meetings
 Hide your lawyers!!
 unless there is a clear legal issue -- and, if you do, FDA will bring in
theirs
 Outside Experts –
 Use judiciously
 Ensure qualified – and vette their publications and other statements
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Working With FDA …

Late in Review Process– a tip:
 Prepare For An Advisory Committee/Panel Meeting,
Even If One Is Not Likely –
 Helps you to know your arguments on key issues before they arise
(as they often do) should the regulatory agencies signal a need to
negotiate on your submission
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Working With FDA …

Listen!!
 If You Get Regulatory Agency Advice -- Do It!
(well, almost all the time)
 Failure to adhere to any given advice may only subsequently antagonize the
reviewer.
 Caveat -- If you don’t want to do it or think it’s wrong, engage FDA
promptly to gain its buy-in to your position
 Don’t just ignore FDA and go down your own path

Keep your Promises!!
 A sure way to lose credibility – fail to deliver what you promised
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Clinical Trial Execution

Unfortunate, But Often Accurate Generalization --
failure to design and execute study properly too often
characterizes clinical studies at both small and even large
companies
 Inadequate Toxicology Review Prior to Phase I – use an
outside set of eyes if you can
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Clinical Trials …

Poor Design Issues:
 Result -- leads to protocol violations, deviations and half
effective amendments.
 Consequence of deviations, violations -- study “mutates” –
 progress and treatment of first patient barely resembles last patient
-- study population no longer homogeneous
 Final Mutation -- heterogeneous population defies statistical analysis
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Clinical Trials …

Primary Efficacy Endpoints
 Must do adequate Phase 2 studies…dose, dosing regimens, etc. so that
you aren’t second guessing the appropriate dose in Phase 3
 Be Sure Endpoint Is Validated And Acceptable to FDA
 this includes Phase 2b studies

Involve Statisticians In Clinical Design
 Don’t Delay Until Problem Occurs
 Can Help Define The Study Design At The Correct Stage -- speeds
clinical development process
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Clinical Trials …

Key Opinion Leaders:
 Include KOL’s In Clinical Program
 But, don’t blindly let them design the protocol
 But, don’t let Sales/Marketing drive this
 Stark Act issues – distinguish KOL’s from big ‘scribers
 Financial disclosure challenges – cost of studies vs. consulting
fees
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CMC/Design Specification Issues

Design Product Physical Characteristics To Be As Robust As Possible
 Validate And Qualify –
 Drugs -- e.g., dosage form, stability, content uniformity
 Devices – choice of biomaterials; design changes
 Drugs -- keep A Lot History/Change Control System At The Earliest Stage -
- even if very rudimentary form (such as memos to file)– it may be important later
to track back to what was done even at early stages
 Ideally just as soon as something in "R" starts to show potential of interest to those
in "D"!
 Do even if project is still under "Research" control -- don't wait for a refined QA
system to be implemented or for the researchers to be trained in drug development
concepts.
 Devices – Design History File is key – make sure it is well-kept
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CMC/Design Specification Issues

Plan For Commercial Scale Production Early –
 pre-NDA meeting is no time to learn that you need additional stability or a
bioequivalence study to qualify your commercial product (e.g., larger scale,
imprinting/debossing etc.) against the one studied in development.

Track And Validate Changes In Processing And
Formulations/Designs – ensure studied process/formulation will
support commercial process/formulation
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Safety

Detect As Early As Possible
 Use Newer In Vitro Approaches to predict at potential
safety problems (if possible)
 Cardiovascular Signals – Key Driver (e.g., HERG)

Dose-Response Data - Seek Early On In Animal Studies (if possible)
 Vital To Ensure Proper Dose for Phase II
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Labeling

FDA Concurrence On Main Indication/Intended Use - NOT Enough -- Must Get Sign-off on Other Key
Label Claims –
 Example -- secondary endpoints

TIP -- Prepare optimal labeling and at least three defensible
fall-back positions for each key statement.
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Outside Vendors

Audit Aggressively
 Prequalification – key – have a robust SOP for doing so
 Use outside auditors if you can – more objective; not subject to the “heat”
or “dance” of the deal
 Types: CROs, clinical investigators, contract manufacturers, API and
component makers, nonclinical testing facilities
 Don’t Miss Any
 Joint venture partners - e.g., Cialis® - Lilly manufacturing plant problems -
delayed about one year
 MDS problems – analytical testing – delayed approvals
 IRBs - have been shut down in past
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Outside Vendors …

How To Handle:
 Audit SOPs, Training, Documentation & Follow-Up – keys to auditing
 If don’t have internal expertise, hire qualified consultants (of course, you
have to qualify them)
 Insist Contractors Include Sponsor On Document Reviews, such as
 Clinical Protocols
 Manufacturing-related [master and production batch records, analytical data,
stability protocols/data, deviations, etc.]
 Nonclinical [draft protocols and reports] documents.
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Outside Vendors …

How To Handle:
 Keep Control -- do not let a contractor direct your project
 Avoid “CRO Creep” – use stringent and explicit contract
language
 Liability - even when you outsource, you are ultimately liable
for what happens -- you still need to have systems and people
in place to ensure your vendors are working correctly
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Ingredients – Active And Inactive

Assure Adequate Supplies -- of all components of the
product, packaging, etc.

Naturally-Derived Products
 Supply Chain And Cost-of-goods – key issues down the
road as well as with potential investors –
 Investigate Alternative (e.g., synthetic) Sources

Challenge or Opportunity? –
 synthetic source may require new clinicals
 may delay or bar generic competition
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Final Sermons

Don't Bury Your Head To Problems -- investigate and
disclose promptly

Don't Fall Madly In Love With Your Technology –
 You Have To Prove Safety And Effectiveness –

"I just know it works" -- not the standard in the Federal
Food, Drug, and Cosmetic Act –
… your baby may have some warts
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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 760.633.3343
Fax 760.454.2979
Cell 760.815.4762
[email protected]
www.weinberggroup.com
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About your speaker…
Michael A. Swit, Esq., is a Vice President at THE WEINBERG GROUP, where he develops and ensures the
execution of a broad array of regulatory and other services to drug, biologics and medical device/diagnostic clients
seeking to market products in the United States. His expertise includes product development strategies, compliance
and enforcement initiatives, recalls and crisis management, submissions and related traditional FDA regulatory
activities, labeling and advertising, and clinical research efforts.
Mr. Swit has been addressing critical FDA legal and regulatory issues since 1984. His 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. A magna cum laude graduate of Bowdoin College, he received his
law degree from Emory University Law School and is a member of the California, D.C. and Virginia bars.
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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.
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