KEY CURRENT ISSUES IN EUROPEAN REGULATON

Michael A. Swit, Esq.Vice President, Life Sciences

Pharmaceutical Education Associates

From Pipeline to Product: Navigating the FDA Approval

Process

Alexandria, VANovember 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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LEGISLATIONArticle 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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NONCLINICALNonclinical 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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COSTSFee level

Area of Advice

Initial advice

Follow –upadvice

III Q, S and CDQ and CDS and CD

€ 69,600$ 101,600

€ 34,800$ 50,808

II CDQ and S

€ 52,200$ 76,212

€ 26,100$ 38,106

I QS

€ 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 1Limits Micro Small Medium

Employees

AND

10 50 250

Annual TurnoverAND / 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 SciencesTHE WEINBERG GROUP INC.

336 North Coast Hwy. 101Suite C

Encinitas, CA 92024Phone 760.633.3343

Fax 760.633.3501Cell 760.815.4762

D.C. Office 202.730.4123michael.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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