Ensuring FDA Regulatory Success for Biomedical Companies -- Key Lessons for Start-Ups

Solving FDA Legal Challenges for the Life of a Life Sciences Company -1- www.fdacounsel.com
LAW OFFICES OF MICHAEL A. SWIT
Ensuring FDA Regulatory Success for
Biomedical Companies
Key Lessons for Start-Ups
Michael A. Swit, Esq.
Vice President, Life Sciences
Supporting Materials for Michael Swit’s Panel Remarks
at
Workshop Co-sponsored by the Orange County Regulatory
Affairs (OCRA) Discussion Group and the Small Business
Development Center @ UCI Applied Innovation (SBDC)
October 25, 2018
Irvine, California

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

FDA's Three Key Development Roles
▪ "Gatekeeper" to the marketplace -- the new drug and
device approval/clearance processes
▪ "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

4
Where The Pitfalls Lie
• Overall Planning
• Working With FDA
• Clinical Trial Execution
• CMC and Design History Issues
• Safety Issues
• Labeling
• Ingredients – Active And Inactive; Components for Medical
Devices
• Final Sermons

5
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)

6
Overall Planning …
• Understand What Your Product Is (yes, sometimes, it is
not clear):
– Drug
– Biologic (but regulated as a drug in U.S.)
– Device
– Combination Product
– Cosmetic
– Dietary Supplement
– Food
• And, remember, often it is what you say about a product
that determines what it is …
– For example, contrast:
• Water – labeled to drink = food
• Water – labeled to cure cancer = drug

7
• 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.
• Medical device design controls SOPs – when they apply; what to do before
hand

8
• 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 (and can get
reimbursed for)
– 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 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

9
• 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

10
• 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)
• Embed outcomes measures in your clinical studies at the front end
– thus need to work with payers before clinicals to ensure that you
include those measures
– Going back later to get that data will be expensive and delaying

11
• 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

12
• 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]

13
Coordinating with EU
• Start planning early for simultaneous efforts
• Drug approvals – systems in EU 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
• Other regions – also require careful coordination and
expertise

14
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.,
• Drugs -- Breakthrough, Fast Track, Accelerated Approval,
Orphan Drug, Special Protocol Assessments (but be careful on
this)
• Devices – Abbreviated 510k, Special 510(k), HDE, etc.

15
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

16
• Safety is Lynchpin Today –
– Focus On Signals/AE’s Early
• Ensure personnel evaluating are qualified
– “REMS” –
• “Risk Evaluation and Mitigation Strategies”
• Can be required 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

17
• Logistics:
– Understand IND and IDE Regulations – especially on
changes:
• Amendments
• Annual reports
– Use the Pre-IND (drugs/biologics) and Pre-Submission
(devices) processes – and later meetings such as End of Phase 2
and pre-NDA/PMA 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.

18
• 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

19
• 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

20
• Formal Meetings
– Consider technology assistance -- for advisory meetings
– Hide your lawyers!!
• unless there is a clear legal issue -- and, if you do bring, FDA
will bring in theirs
• SCIENCE should drive meetings
– Outside Experts –
• Use judiciously
• Ensure qualified – and review their publications and other
statements to make sure they have not said something that
undermines your position

21
• 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

22
• 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

23
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

24
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`

25
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

26
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, as can lead to:
• Stark Act issues – distinguish KOL’s from big ‘scribers
• Financial disclosure challenges – cost of studies vs.
consulting fees
– FDA Financial Disclosure rules – 21 CFR Part 54
– Sunshine Act requirements

27
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

28
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

29
Safety
• Detect Issues As Early As Possible
– Use Newer In Vitro Approaches to predict 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

30
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 fallback positions for each key statement.

31
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 approval about one year
• Contract Lab (e.g., MDS) problems – analytical testing – delayed
approvals
• IRBs - have been shut down in past
• Quality Agreements – essential – must be detailed,
robust

32
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 also)
– 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.

33
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

34
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

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

Questions?
• Call or e-mail:
Michael A. Swit, Esq.
San Diego, California
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 Illumina, Inc., the world’s leading developer of gene sequencing technologies.
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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