Presentation to the Pharmaceutical Education Associates "From Pipeline to Product: Navigating the FDA Approval Process" Conference in Alexandria, VA, on November 30, 2007, with an emphasis on: SCIENTIFIC ADVICE SMALL-TO-MEDIUM ENTERPRISES (SME’s) TIPS & PITFALLS

1. KEY CURRENT ISSUES IN
EUROPEAN REGULATION
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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WHAT WE WILL COVER
• SCIENTIFIC ADVICE
• SMALL-TO-MEDIUM ENTERPRISES
(SME’s)
• TIPS & PITFALLS

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SCIENTIFIC ADVICE

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LEGISLATION
Article 57(1) (n) of Regulation (EC) No 726/2004:
• “the Agency, acting particularly through its committees, shall
undertake the following tasks: Advising undertakings on the
conduct of the various tests and trials necessary to
demonstrate the quality, safety and efficacy of medicinal
products”
Purpose
• To ensure CHMP support, through SAWP, to companies
developing medicinal products
• To reduce the uncertainty of the Marketing Authorisation
outcome

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SCIENTIFIC ADVICE WORKING
PARTY
• Scientific Advice Working Party (SAWP)
– Internal processes within CHMP to allow for advice
to be given to all companies, in particular, small and
medium sized enterprises
– Provides both general and in-depth Scientific Advice
through experts within national Regulatory Agencies and
from consultants
– Others involved -- patient organizations and health-care
professionals associations

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SCIENTIFIC ADVICE WORKING
PARTY
• Areas of particular interest
– Products intended for the new mandatory centralized
procedure
– Emerging therapies and New therapies
– Safety aspects
– Conditional marketing authorizations
– Authorizations under Exceptional Circumstances
– Significant clinical benefit for orphan drugs

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SCIENTIFIC ADVICE AREAS
• Frequency of requests for Scientific Advice -
- by CTD areas:
– Quality (i.e., CMC) – 20%
– Nonclinical – 30%
– Clinical – 50%
• Most issues at Marketing Authorisation
stage -- relate to clinical efficacy

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SCIENTIFIC ADVICE PROCESS
• Timing of request
– At any sage of development process
– Not specific phase – unlike FDA (eg pre-IND, end of Phase II)
• Process for obtaining advice
– Request
– Presubmission meeting (not essential but valuable for fine tuning
questions)
– Formal submission of data
– Potential face to face meeting

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QUALITY (CMC)
Quality requests (20%)
• Comparability (38%)
• Change in manufacturing process
• Biotechnology ‘similarity’ issues
• Change of formulation
• Stability (15%)
• TSE, viral safety issues (7%)

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NONCLINICAL
Nonclinical requests (30%)
• Bridging toxicology programmes (eg new indication for existing
molecule) 16%
• Carcinogenicity (waivers, timing, models) 38%
• Reproduction toxicology (waivers, timing) 21%
• Studies in juvenile animals (eg linked to paediatric development
issues) 3%
• Pharmacological models for biological/biotech products

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CLINICAL
Clinical (50%)
• Clinical efficacy endpoints
– Primary (75% requests)
• Choice, acceptability, relevance
• Surrogate endpoints as opposed to hard clinical
endpoints
• Composite endpoints
– Secondary (30%)

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USEFULNESS OF S.A.
• Does Scientific Advice have an impact?
– SA seems to correlate with positive outcome on
Marketing Authorisation
• Not a guarantee for a positive outcome
– SA is not a means of changing data
– SA is useful if advice is followed (do not ignore
recommendations)
– SA cannot have an impact if relevant issue was
not part of the SA request

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FEES
• Fees payable for Scientific Advice
• Cost dependent on extent of enquiry
– Clinical development (CD)
– Quality (Q)
– Safety (S)
• Fees reduced for companies with SME status
(10%)
• No charge for advice on Orphan Products (SA
termed Protocol Assistance)

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COSTS
Fee
level
Area of Advice Initial
advice
Follow –up
advice
III Q, S and CD
Q and CD
S and CD
€ 69,600
$ 101,600
€ 34,800
$ 50,808
II CD
Q and S
€ 52,200
$ 76,212
€ 26,100
$ 38,106
I Q
S
€ 34,800
$ 50,808
€ 17,400
$ 25,404

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TIMELINES
• Formal request submitted
– On day -30, or day -60 if pre-submission meeting requested
• Pre-submission meeting (still optional but advisable)
– Systematic involvement of coordinators and experts
– Receive early feedback on content
– Fine tune questions
– Increase quality of request before start of procedure
• Day 0 – start of procedure
• By Day 70 – adoption of final letter (maximum time)
– Following 3 SAWP meetings (expert appointment, discussion of report,
final meeting)
• Possibility of finalization by Day 40
– Following 3 SAWP meetings (expert appointment, discussion of report)

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FOLLOW-UP REQUEST
• Follow-up advice
– Any subsequent request falling within the same
therapeutic indication and areas as the initial request
– Not restricted to the questions raised in the initial request
– Initial request may be only on the dose-finding study,
subsequent request on Phase III will attract only a
reduced follow-up fee
– Areas includes quality or nonclinical or clinical including
pharmacovigilance / risk management aspects

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FOLLOW-UP REQUESTS
• Ensure continuity of support from the
CHMP during development of medicinal
products
• Should reduce the uncertainty of the
Marketing Authorization outcome
• Permit more interactions between
development companies and SAWP

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SMALL-TO-MEDIUM
ENTERPRISES (SME’s)

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LEGAL SOURCE
• Commission Recommendation
2003/361
– Defines SME:
• Micro, Small and Medium
– Provides Framework for Incentives
• Commission Regulation 2049/2005 -- Applies
Recommendation 2003/361 to Human and Veterinary
Medicinal Products when Submitted via the Centralised
Procedure
– Does Not Apply to Authorisation Applications via National Procedures.
– Some EU Member States have Limited SME Initiatives (Denmark, Germany,
Portugal, Sweden and UK)

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SME DEFINITIONS 1
Limits Micro Small Medium
Employees
AND
10 50 250
Annual
Turnover
AND / OR
€2 million
$3 million
€10 million
$15 million
€50 million
$73 million
Annual
Balance
Sheet
€2 million
$3 million
€10 million
$15 million
€43 million
$63 million

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SME DEFINITIONS 2
Autonomous < 25%
Partner 25 – 50%
Linked > 50%

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SME STATUS
• Restricted to companies “established” in the
EEA
– defined as having a legal presence in an EEA Member State
• “… permanent legal structure which is formed in accordance with
the laws of the EU or EEA member state …”
• In practice, SME Status is not Limited to
Companies with Local Offices in the EEA --
Consultants Established in the EEA can act on behalf
of Companies from any Country if the company
otherwise qualifies

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SME APPLICATION PROCESS
• Self-Certification re Number of Employees
and Provision of Appropriate Financial
Information, normally in the form of the
Latest Audited Annual Report
• No fixed time limit for approval, but normally
within three to four weeks

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KEY SME BENEFITS
• Fee Reductions for Scientific Advice
• Deferral of MAA Fee and related Inspections
• Conditional Fee Exemption
• Assistance with Translations

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SME BENEFITS
• Fee Reduction for Scientific Advice -- 90%
Reduction for Initial and Repeat Advice in all
areas – CMC, Nonclincal, Clinical
€3,500 - €7,000
$5,000 - $10,000
• Deferral of MAA Fee and related Inspection
Fees -- can be deferred until 45 Days after
Approval

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SME BENEFITS
• Conditional Fee Exemption -- where
Scientific Advice is followed and a Marketing
Authorisation Application is not successful
• Assistance with Translations -- SmPC,
Package Labels, Package Inserts
– EEA = 30 Countries and 23 Languages

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BENEFIT PARAMETERS
• Equal Benefits for all SMEs
(Micro, Small, Medium)
• Most Favourable Benefit Applies
(SME versus Orphan)
• Benefits not Cumulative
(Not SME and Orphan)

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SME STATUS SUMMARY
• SME Status available to any company, within the
Headcount and Financial Limits
• Companies in the EEA Apply Directly
• Companies outside the EEA apply via an Agent
• Significant Fee Reductions and Deferrals

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EUROPEAN TIPS & PITFALLS
• Plan Out Timelines For Each Country
– CTA needed in all member states
– May be additional committees for gene therapy, GMOs, etc.
• Set Your Regulatory Submission Plan Carefully
– Identify coordinating centers 'strategically'
– Prepare documents for EC and Competent Authority
submissions – evaluate requirements
• for translation
• and any additional documents.
• number of copies required.

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TIPS & PITFALLS …
• Product Release -- If Company Has No
'Presence' In The EU, Qualified Person (“QP”)
Release Of Your Product Will Be Required.
• Product Distribution Requirements,
Including Labeling -- considered and planned
for in advance.

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TIPS & PITFALLS …
• Seek Advice In Parallel With U.S. If Possible
– EMEA Or Individual State.
– EU May Approve Where U.S. Does Not
– EU advice also can help “inform” FDA strategy
– Key Opinion Leaders: are especially important in
Europe

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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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