Presentation to the Pharmaceutical Education Associates "From Pipeline to Product: Navigating the FDA Approval Process" conference in Alexandria, VA, on November 30, 2007, with a focus on: • Overall Planning • Working With FDA • Clinical Trial Execution • CMC Issues • Safety Issues • Labeling • Ingredients –Active And Inactive

1. REGULATORY AND OTHER
PITFALLS IN DRUG
DEVELOPMENT
Michael A. Swit, Esq.
Vice President, Life Sciences
Pharmaceutical Education Associates
From Pipeline to Product: Navigating
the FDA Approval Process
Alexandria, VA
November 30, 2007

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Disclaimer
• This outline is intended to support an oral
briefing and should not be relied upon solely to
support any conclusion of fact or law.
• The views reflected in this presentation are solely
those of the presenter and do not necessarily
reflect the position of my firm, any of its clients,
or any of my friends and colleagues that
contributed their thoughts to this presentation.

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WHERE THE PITFALLS LIE
• Overall Planning
• Working With FDA
• Clinical Trial Execution
• CMC Issues
• Safety Issues
• Labeling
• Ingredients – Active And Inactive
• 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.

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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 Has Been Rigorously Reviewed -- so as to
optimize your chances when going into humans.
– Once Clinical Evaluation With A Compound 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.

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OVERALL PLANNING …
• Make Sure Regulatory, Clinical, And Sales &
Marketing Are All Talking Early On –
– Ensure Indication (Thus, Endpoints) Being Studied Is
One You Want To Sell
– Some Consideration
• 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 non-inferiority -- hence failed development program…
• Indication 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
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 –
clinicals will be needed (FDA/FTC)

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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
• 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

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OVERALL PLANNING …
• Management
– Must Understand Process.
– Must Support Company's Quality System, Especially As
A Company Matures.
– 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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WORKING WITH FDA
• Early interaction -- essential to understanding
your path and what you need in your kitbag
– 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 …
• 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

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WORKING WITH FDA …
• Logistics:
– Understand IND Regulations – especially on changes:
• Amendments
• Annual reports
– 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
– Consider technology assistance -- for advisory meetings
– Hide your lawyers!!
• unless there is a clear legal issue -- and 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 Meeting,
Even If One Is Not Likely –
• helps to marshall your arguments before hand should the
regulatory agencies signal a need to negotiate.

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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 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 ISSUES
• Design Product Physical Characteristics To Be As
Robust As Possible
– Validate And Qualify – e.g., dosage form, stability, content
uniformity
– 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.

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CMC 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 – 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 --
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
– Types: CROs, clinical investigators, contract
manufacturers, API 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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Call, e-mail, fax or write:
Michael A. Swit, Esq.
Vice President, Life Sciences
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?

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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 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.

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