Webinar sponsored by NanoTecNexus (www.http://nanotecnexus.org/) on contemporary regulatory issues in drug development, with an emphasis on:  Overall Planning  Working With FDA  Clinical Trial Execution  CMC Issues  Safety Issues  Labeling  Ingredients – Active And Inactive

1. A Webinar Sponsored by NanoTecNexus
Michael A. Swit, Esq., Vice President
4 March 2010
Drug Development in Today's
Regulatory Environment"

2. 1
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.

3. 2
WHERE THE PITFALLS LIE
 Overall Planning
 Working With FDA
 Clinical Trial Execution
 CMC Issues
 Safety Issues
 Labeling
 Ingredients – Active And Inactive
 Final Sermons

4. 3
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.

5. 4
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.

6. 5
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 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 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

7. 6
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 patent 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

8. 7
OVERALL PLANNING …
 Understand Approval Is Not Enough, Somebody
Has to Pay for It!! - coverage (on formulary) and
reimbursement (at a reasonable co-pay 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)

9. 8
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
 Global Development – try to coordinate -- FDA may be the “gold
standard” – but that may be irrelevant in EU, Japan, etc.

10. 9
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]

11. 10
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, Special Protocol Assessments (but be careful on this)

12. 11
WORKING WITH FDA …
 Ensure You Get Agency Agreement On Exactly What Is The
Indication – will drive related labeling language, especially those
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

13. 12
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

14. 13
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.

15. 14
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 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

16. 15
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

17. 16
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.

18. 17
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
 Excellent science presented clearly -- essential
 Keep your Promises!!
 A sure way to lose credibility – fail to deliver what you promised

19. 18
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

20. 19
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

21. 20
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

22. 21
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
 Physicians Payments Sunshine Act – legislation lurking in Health Care
Reform bills

23. 22
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.

24. 23
CMC ISSUES …
 Plan For Commercial Scale Production Early –
 pre-NDA filing 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

25. 24
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

26. 25
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.

27. 26
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
 Raw Material Suppliers – especially API – you do not want a
Heparin scenario

28. 27
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.

29. 28
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

30. 29
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

31. 30
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

32. 31
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
michael.swit@weinberggroup.com
www.weinberggroup.com
Questions?

33. 32
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 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. He received his A.B., magna cum laude, with high
honors in history, from Bowdoin College and his law degree from Emory University.

34. 33
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