Arrowhead Drug Delivery Summit

San FranciscoMay 14, 2009

Michael A. Swit, Esq.Vice President

Drug Delivery -- Perspectives on the FDA Regulatory Environment

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.

What We Will Cover

The FDA World – how is it changing? Combination Product Regulation – where

drug delivery intersects with agency purview How FDA approaches combination products Real time examples

Getting prepared -- How to focus on FDA regulatory issues in drug delivery

The FDA World

“Global” Environment Obama Administration – what does it foretell

Universal health care …? Comparative effectiveness – keep an eye on this Increased enforcement/compliance activity – get

your house in order – beware the “Fear of Wiley” FDA Issues

New commissioner – Margaret Hamburg nominated Cleared yesterday by Senate H.E.L.P. Committee; full

confirmation not set yet any biases/predilections?

Reported she is interested in food safety Deputy Commissioner – Josh Sharfstein – ex-

Waxman staffer

FDA Environment -- Drugs Safety – mantra – life changed on September 30,

2004 Result –

FDA is very risk averse “Show me” Don’t get called up in front of Congress for not approving a

drug FDAAA -- increased emphasis on risk/benefit analyses

and risk management Can mandate a REMS – Risk Evaluation and Mitigation

Strategy Can mandate post-approval studies

Industry – must improve early detection of drug event signals

FDA Environment – Devices CDRH – under fire by Capitol Hill – coercion of

reviewers by upper management – impact??? Changes at the top?

CDRH Director– staying? House in New Mexico ODE Director – also “implicated” OIVD – Gutman left – where to?

Prolonged Congressional inquiry -- very disruptive as diverts resources

Pressures FDA to be much more conservative – e.g., device companies may be required to submit IDEs and resultant clinical data to support the 510(k) process Alpert – agrees -- more data; less risk tolerance.

Sharfstein just ordered CDRH to re-examine clearance of knee surgery device allegedly secured in part due to Congressional pressure

Device Approval/Marketing Issues

510k Process – in spotlight GAO report – required by FDAAA

Includes a focus on FDA’s failure to require PMAs or reclassify a number of pre-’76 devices as required by the 1990 Safe Medical Devices Act If put in Class III, PMA’s will be needed None were IVDs

Focuses on “High risk device” should be under PMA New intended uses – only found in 1% of 510k’s New tech. characteristics – only found in 15%

Partial result – call for data on pre-76 devices – April 9

Lingering issue – “substantial equivalence drift”

Device Approval/Marketing Issues …

Anticipate more demand for clinical data for Class II devices

Clinical studies – already hard; could get harder Proposed Physicians Sunshine Act would

require physicians to post the disclosure on a federally run website and if they do not file the fine is pretty hefty. $10,000/day. Disincentive to be an investigator?

Inspections – there is legislative language on Capitol Hill that would require an inspection for every 510k

Combination Products – Where Drug Delivery

Intersects FDA

What Is a Combination Product?

As defined in 21 CFR § 3.2(e), the term combination product includes: (1) A product comprised of two or more regulated components, i.e.,

drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity;

(2) Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products;

(3) A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or

(4) Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.

The Combination Galaxy

Devices PMA/510(k)/IDE QSR MDR

DrugsNDA/INDcGMPAERS

Biologics

BLA/IND

cGMP+

AERS+ Primary Mode of Action

Consultation

Regulations

A Brief History Office of Combination Products (“OCP”)

Created by Medical Device User Fee and Modernization Act (MDUFMA)

Office established on December 24, 2002

OCP given broad oversight responsibilities covering the regulatory life cycle of combination products. Coordinate reviews among FDA Centers Ensure consistency among similar reviews

Section 503(g) of the Act FDA is required to assign a combination product

to a lead Center based on its "primary mode of action“ -- PMOA

PMOA was not defined in the statute or regulations

For some products, PMOA is difficult to identify Early in development (just don't know) Products that have two (or more) completely

different modes of action, neither of which is subordinate to other

Nanotech – additional challenges

PMOA -- Determining Which Center Leads

PMOA = Primary Mode of Action; not defined in statute, but in regulations Final Rule – 8/25/2005; 70 Fed. Reg. 49848

http://www.fda.gov/OHRMS/DOCKETS/98fr/05-16527.pdf

Mode of Action: the means by which a product achieves an intended therapeutic effect or action. 21 CFR 3.2(k)

Three types of modes of action: biological product, device, drug

Combination products typically have more than one identifiable mode of action

PMOA …

Primary mode of action is the single mode of action of a combination product that provides the most important therapeutic action of the combination product. The most important therapeutic action is the mode of action expected to make the greatest contribution to the overall intended therapeutic effects of the combination product. Source: 21 CFR 3.2(m)

The PMOA Decision Tree

If unable to determine most important therapeutic action with reasonable certainty, consider: Consistency: is there an agency component

that regulates other combination products presenting similar questions of S & E with regard to the combination product as a whole?

Safety and Effectiveness: which agency component has the most expertise related to most significant S&E questions presented by combination product?

Not Sure – Requests for Designations (RFDs)

Voluntary Formal Process under 21 CFR Part 3 Seeks to determine:

Classification Assignment Clarification of Regulatory Pathway

If don’t file, FDA may stay review clock while a determination is made

When: Before any application for premarket review As soon as enough info exists for FDA to make a decision

RFD’s … Key sections to focus on:

What is your product? Why would your product be used? How does your product work? What is your product’s most important

therapeutic action? What is the basis for your PMOA analysis? How do you think your product should be

assigned?Why? Use assignment algorithm if appropriate.

RFD’s … OCP reviews RFD’s for completeness If complete, OCP sends acknowledgement letter to

sponsor, and copy of RFD’s to three Center Liaisons Center recommendations due to OCP in 21 days Consultation among OCP, Centers and Office of Chief

Counsel Decision reached, response letter prepared, necessary

clearances obtained Decision must issue within 60 days; if not YOUR

recommendation wins!!

RFD’s … Request for Reconsideration

Submit within 15 days Less than 5 page submission, no new information FDA response within 15 days FDA has been known to change a decision upon

reconsideration Effect of RFD Letter – designated FDA Center can

only be changed without your consent to protect the public health or another compelling reason. Source: 21 CFR 3.9(b)

How Many Applications? Concept Paper on Marketing Applications for Combination

Products http://www.fda.gov/oc/combination/singlesepconpaper.pdf

Basics: PMOA does not ensure application status; but lead Center Single application usually is sufficient Exceptions

One component is already approved, but labeling will need to be changed

Biologics – legally can have separate apps. for components When the components are “separate and complex” – e.g., a

device in combination with a new molecular entity drug/biologic

Where needed to “apply mechanisms to ensure appropriate regulation or unique regulatory requirements” not available under one app. Example: gene therapy

How Many Applications?... You Might Want Two – perhaps:

To qualify for Waxman-Hatch Exclusivity Orphan Drug Status To protect proprietary data if 2 firms are

involved Complex decision tree suggested in concept

paper on how these are handled Examples

Single application – pre-loaded syringes, transdermal patches

Two or more – laser activated drugs, iontophoresis

Drug Delivery Successes at FDA

Neupro Patch – Early Parkinson’s Disease – rotigotine transdermal

InFuse Bone Graft – for filling in missing tooth bone

Methlyphenidate Patch – ADHD in children Emsam Patch – Selegiline for depression Exubera – inhaled insulin –

Not a market success Integrated glucose monitor and insulin

delivery system

Getting Prepared -- Focusing on FDA Regulatory Issues in Drug

Delivery

Be Prepared

“Validate” plans early Take advantage of FDA meeting opportunities

Pre-IND, EOP2, Pre-NDA/BLA filing Pre-IDE

VC’s – will expect you to know what you are doing

But, don’t roll over and accept what FDA says without questions

Don’t Assume Europe and U.S. Think Alike BioSimilars – EU is ahead of U.S. Scientific Advice process

Be Prepared … When does drug delivery become the

PMOA? Historically, with delivery systems, the focus

on the therapeutic moiety But, could the improved delivery be the PMOA? Try to be a PMA – stent precedent allows you

where the drug component does not need an NDA

Know Your Partners Audit them Their problems are yours – e.g., Cialis and Lilly

Ancient Chinese Curse

May You Live In Interesting Times …

(possibly an ancient Chinese Curse)

Call, e-mail, fax or write:

Michael A. Swit, Esq.Vice President

The Weinberg Group Inc.336 North Coast Hwy. 101

Suite CEncinitas, CA 92024

Phone 760.633.3343Fax 760.454.2979Cell 760.815.4762

michael.swit@weinberggroup.comwww.weinberggroup.com

Questions?

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 drug and biologics clients seeking to market products in the United States. His expertise includes FDA development strategies, compliance and enforcement initiatives, recalls and crisis management, submissions and related traditional FDA regulatory activities, labeling and advertising, and clinical research efforts.

Mr. Swit has been addressing critical FDA legal and regulatory issues since 1984. His 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. A magna cum laude graduate of Bowdoin College, he received his law degree from Emory University Law School and is a member of the California, D.C. and Virginia bars.