COMBINATION PRODUCTS – Perspectives on FDA Regulation

Overview of FDA regulation of combination products -- those featuring a drug and a device, a device and a biologic, or a biologic and a drug. Reviews key issues such as Primary Mode of Action, Requests for Designation, and how to handle GMPs and Adverse Event Reporting for combination products.

1. COMBINATION PRODUCTS –
Perspectives on FDA Regulation
Michael A. Swit, Esq.
Vice President, Life Sciences
Biotech Vendor Services
Presents

Orange County Biomedical Day


Irvine, California
September 19, 2007

2. 2
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.

3. 3
The Combination Galaxy

Devices
PMA/510(k)/IDE
QSR
MDR



Drugs
NDA/IND
cGMP
AERS


Biologics
BLA/IND
cGMP+
AERS+

Primary Mode of Action
Consultation
Regulations

4. 4
A Brief History of Combinations
•Combination products statutorily
recognized in Safe Medical Device Act of
1990
•Required assignment to lead center based
on primary mode of action
•Implemented by Chief Mediator and
Ombudsman

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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

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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 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

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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

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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)

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Final PMOA Rule: Constituent Parts
•A constituent part of a combination product has a:
–Biological product mode of action if it acts by means of a virus,
therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or
derivative, allergenic product, or analogous product applicable to the
prevention, treatment, or cure of a disease or condition of human
beings…

–Device mode of action if it meets the definition of device…, it does not
have a biological product mode of action, and it does not achieve its
primary intended purposes through chemical action within or on the
body….and is not dependent on being metabolized for the achievement
of its primary intended purposes

–Drug mode of action if it meets the definition of drug…and it does not
have a biological product or device mode of action.

10. 10
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?

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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

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RFD’s …
•Contents:
–Sponsor information
–Product description
–Proposed use and indications
–Description of primary mode of action
– Recommendation on product classification and
Center with primary jurisdiction
•Source: 21 CFR §3.7(c)
•Guidance on How to Write a RFD (8/2005)
–http://www.fda.gov/oc/combination/Guidance-How%20to%20Write%20an%20RFD.pdf

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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.

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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!!

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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)

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Jurisdictional Decisions -- Examples
•BreathTest Combinations
–http://www.fda.gov/oc/combination/breathtest.html
•Minimal Manipulation of Structural Tissue
–http://www.fda.gov/oc/combination/Minimal%20Manipulation%20JU%20(Final%209-19-06).pdf
•Heparin Catheter Lock-Flush Solutions
–Federal Register of 8/17/2006 -- http://www.fda.gov/OHRMS/DOCKETS/98fr/E6-
13509.htm
–Summary -- http://www.fda.gov/oc/combination/catheter.html
•Metered Dose Inhalers, Spacers and Other Accessories
–http://www.fda.gov/oc/combination/mdiupdate.html
•Drug/Biologic Combinations
–http://www.fda.gov/oc/combination/biologic.html

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Which GMP Rules Apply?
•Guidance on GMPS for Combination Products
–http://www.fda.gov/oc/combination/OCLove1dft.pdf
•Sets forth broad framework for application of
cGMP to combination products
•Each constituent part (drug, device, and/or
biological product) of a combination product is
subject to its governing cGMP regulations
before combination

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GMPs …
•During and after combination, both sets of
cGMP regulations apply (single entity and co-
packaged products*)
•Recognizes that many manufacturing facilities
operate under one type of manufacturing system
•cGMP and QS regulations are generally similar

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GMPs …
•Each regulation also contains key elements based
upon the unique characteristics of the types of
products were designed to address
•Compliance with both sets of regulations can
generally be achieved by using either regulation
–e.g., by using the system in place at a facility and
paying special attention to key issues

20. 20
GMPs …
•If properly implemented, parallel operating
systems (e.g., cGMP and QS) should not be
necessary
•Reasoning: possible to implement a practice
under a general requirement in one set, for
example, that complies with a more specific
requirement of other set

21. 21
GMPs …
•Guidance -- identifies key provisions of cGMP
and QS regulations that differ in specificity and
that should be carefully considered by
manufacturer
•For example, if operating under Device cGMP
Quality System:
–Design controls (21 CFR 820.30)
–Purchasing controls (21 CFR 820.50)
–CAPA (820.100)

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GMPs …
•For example, if operating under Drug GMP system:
–Testing and approval/rejection of components (21 CFR
211.84)
–Calculation of yield (21 CFR 211.103)
–Expiration dating (21 CFR 211.137)
–Stability testing (21 CFR 211.166)
–Containers and closures (21 CFR 211.84)
•Ultimately – the two systems are being harmonized

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Future of GMPs …
•Unified Agenda published 4/24/06 (71 Fed.
Reg. No. 78, 22565 (2006)
•Announces plan to issue Proposed Rule, Current
Good Manufacturing Practice for Combination
Products
•Purpose: clarify and streamline regulatory
scheme

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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

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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

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User Fees – Can I Pay the Least
Amount?
•Guidance on User Fees for Combination Products
– April 2005
–http://www.fda.gov/oc/combination/userfee.pdf
•Basics
–Depends on type and # of applications (see prior slide)
–If two applications submitted voluntarily, pay two fees
–If two applications REQUIRED, still pay two fees
•“Innovative Product Waiver” – consider seeking

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Resources
•List of Jurisdictional Determinations – By Assigned
Center
–http://www.fda.gov/oc/combination/determinations.html
•Guidance on Early Development Considerations for
Innovative Combination Products (9/2006)
–http://www.fda.gov/oc/combination/innovative.pdf
•Guidance on How to Write a RFD (8/2005)
–http://www.fda.gov/oc/combination/Guidance-How%20to%20Write%20an%20RFD.pdf
•Final Rule on “Primary Mode of Action” – 8/25/2005;
70 Fed. Reg. 49848
–http://www.fda.gov/OHRMS/DOCKETS/98fr/05-16527.pdf
•Concept Paper on Handling of Adverse Events
–http://www.fda.gov/oc/combination/adveventconpaper.pdf

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Resources …
•Overview of the Office of Combination Products
–http://www.fda.gov/oc/combination/overview.html
•Frequently Asked Questions on Combination Products
–http://www.fda.gov/oc/combination/faqs.html#_Toc88444686
•Other Types of Combinations (e.g., Drug/Cosmetic)
–http://www.fda.gov/oc/combination/other_combinations.html
•List of Recent Combination Product Approvals
–http://www.fda.gov/oc/combination/approvals.html
•Recent Presentations by FDA on Combination
Products
–http://www.fda.gov/oc/combination/presentations/default.htm

29. 29
Resources …
Joanne Less, Ph.D., Acting Director
Office of Combination Products
Food and Drug Administration
15800 Crabbs Branch Way (HFG-3)
Suite 200
Rockville, MD 20855
[phone]
[phone] fax
email: [email protected]

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Redacted Decisions on RFD’s
http://www.fda.gov/oc/combination/rfd.html
•RFD 1992.004 -- Photofrin System [PDF 87KB]
•RFD 1992.012 – SonoRx [PDF 49KB] [Text]
•RFD 1992.013 – Compound Benzoin Tincture [PDF 43KB]
•RFD 1992.015 – Gliatech [PDF 42KB]
•RFD 1992.019 – GenESA Arbutamine Injection System [PDF 74KB]
•RFD 1992.020 – ARTZ [PDF 47KB]
•RFD 1992.029 – Pulse Spray Injector [PDF 54KB]
•RFD 1993.004 – Photophoresis System [PDF 94KB]
•RFD 1993.009 – Alprostadil with Self-Injection System [PDF 65KB] [Text]
•RFD 1993.015 -- Viringe Catheter Flush Device [PDF 64KB]
•RFD 1994.001 – Intestinal Permeability Test System [PDF 62KB]
•RFD 1994.015 – 13C-Urea Breath Test [PDF 112KB]
•RFD 1994.016 – Lidocaine-Epinephrine Iontophoretic Drug Delivery System [PDF
78KB]
•RFD 1995.002 – LiDCo Indicator Dilution Cardiac Output System [PDF 75KB]
•RFD 1995.003 -- Prefilled Fentanyl Delivery System [PDF 69KB]

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Redacted Decisions on RFD’s …
•RFD 1995.014 – SmartMist™ Asthma Management System [PDF 74KB]
•RFD 1995.015 – Tissue Bone Matrix™ Sponge [PDF 375KB]
•RFD 1995.023 -- AxSym™ Hepatitis Test Kits [PDF 69KB]
•RFD 1996.006 – ProCount™ Progenitor Cell Enumeration Kit [PDF 85KB]
•RFD 1996.010 – TheraSphere® Administration System [PDF 77KB]
•RFD 1996.014 -- Hemostatic Agent [PDF 72KB]
•RFD 1996.016 – 13C-Urea Blood Test [PDF 95KB]
•RFD 1996.019 – RESPIFLO Sterile Water for Inhalation Therapy [PDF 87KB]
•RFD 1996.020 – RESPIFLO/S Sterile Water with Saline for Inhalation Therapy
[PDF 87KB]
•RFD 1996.029 – STELLer™ CD34+ Test Kit used with IMAGN® 2000
Instrument [PDF 58KB]
•RFD 1996.032 – HIV-1 Urine EIA Test Kit [PDF 90KB]
•RFD 1997.005 – Sorbastace [PDF 65KB]
•RFD 1997.006 -- Vitros Hepatitis Immunodiagnostic Kits [PDF 97KB]

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Redacted Decisions on RFD’s …
•RFD 1998.002 – Atrisorb-D Barrier Kit [PDF 85KB]
•RFD 1998.003 – Breath ID Test Kit [PDF 91KB]
•RFD 1998.008 – Nupro® Prophy Paste with Fluoride and Triclosan [PDF 90KB]
•RFD 1998.018 – Sealouette™ Sealant Applicator [PDF 87KB]
•RFD 1998.022 – FibriJet Surgical Sealant Applicator [PDF 88KB]
•RFD 1999.004 -- Diagnostic for Glucan in Blood [PDF 77KB]
•RFD 1999.009 – Seal & Protect™ Protective Sealant for Exposed Dentine [PDF 93KB]
•RFD 1999.014 – Wound Dressing [PDF 91KB]
•RFD 1999.015 – Nupro® Prophy Paste with Fluoride and Triclosan [PDF 85KB]
•RFD 2000.006 – Sirolimus-Coated BX VELOCITY™ Balloon-Expandable Stent [PDF
96KB]
•RFD 2000.009 – Trypan Blue Ophthalmic Surgical Marker [PDF 350KB]
•RFD 2000.023 – PEGASYS® (pegylated interferon alfa-2a) with COPEGUS (ribavirin)
[PDF 104KB]
•RFD 2001.004 -- Accessory to SynchroMed Infusion System [PDF 109KB]

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Redacted Decisions on RFD’s …
•RFD 2001.006 – Paclitaxel-Eluting Stent [PDF 102KB]
•RFD 2001.016 -- Amniotic Membrane for Ocular Surface Reconstruction [PDF 118KB]
•RFD 2001.018 – DBX® [PDF 125KB]
•RFD 2001.020 – Allomatrix™ [PDF 119KB]
•RFD 2002.018 -- FloSeal [PDF 217KB]
•RFD 2002.031 – Blow Fly Larvae (Medical Maggots) [PDF 188KB]
•RFD 2002.038 -- Normocarb [PDF 457KB]
•RFD 2003.024 – pH Tampon [PDF 160KB]
•RFD 2004.013 – Decapinol® Oral Rinse [PDF 91KB]
•RFD 2004.014 -- ViziLite-Blue Oral Exam Kit [PDF 159KB]
•RFD 2004.016 -- Colloss E Bone Void Filler [PDF 95KB]
•RFD 2004.033 -- Wart Removal System [PDF 117KB]
•RFD 2004.039 -- Innocor [PDF 79KB]
•RFD 2004.042 – SPY™ Intra-Operative Imaging System [PDF 150KB]
•RFD 2004.053 – Epi-Max Impregnated Wound Dressing [PDF 131KB]
•RFD 2004.066 – Wound Cleanser [PDF 97KB]
•RFD 2005.003 – Sucralfate HCl Topical Paste [PDF 107KB]
•RFD 2005.005 – Misty™ Wound Treatment System [PDF 97KB]

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Call, e-mail, fax or write:

Michael A. Swit, Esq.
Vice President
THE WEINBERG GROUP INC.
1422 Caminito Septimo
Cardiff by the Sea, CA 92007
Phone [phone]
Fax [phone]
Cell 760.815.4762
[email protected]
www.weinberggroup.com
Questions?

35. 35
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, medical device, IVD, and biologics clients –
including combination products -- seeking to market products in the United States and Europe. His expertise includes
FDA and other 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 (inactive) of the California, D.C. and Virginia bars.

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For more than twenty-five years, leading companies have depended
on THE WEINBERG GROUP when their products are at risk.
Our technical, scientific and regulatory experts deliver the crucial
results that get products to market and keep them there.

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