Combination Products, Orphan Drugs, and OTC Drugs

Solving FDA Legal Challenges for the Life of a Life Sciences Company -1- www.fdacounsel.com
LAW OFFICES OF MICHAEL A. SWIT
Combination Products, Orphan Drugs and
OTC Drugs
SDRAN RAC Review Course
July 26, 2018
Michael A. Swit, Esq.

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

Our Topics Today
➢ Combination Products
➢ OTC Drugs
➢ Orphan Drugs
3

COMBINATION PRODUCTS
4

➢ A Brief History of Combination Product Regulation
➢ Primary Mode of Action (PMOA) – The Key
Lynchpin to FDA’s Regulatory Regime for
Combination Products
➢ The Request for Designation (RFD) Process
➢ GMPs
➢ Post-Market Safety Reporting
➢ How Many Applications to File?
➢ User Fees
What We Will Cover
5

➢ As defined in 21 CFR § 3.2(e), the term combination product
includes:
➢ 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;
➢ 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;
➢ 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
➢ 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.
What Is a Combination Product?
6

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

➢ Safe Medical Device Act of 1990 -- combination
products first statutorily recognized
– Required assignment to lead center based on Primary Mode of
Action (“PMOA”)
– Implemented by Chief Mediator and Ombudsman
➢ Office of Combination Products (“OCP”)
– Created by Medical Device User Fee and Modernization Act
(MDUFMA) – 2002
– OCP given broad oversight responsibilities covering the
regulatory life cycle of combination products.
• Coordinate reviews among FDA Centers
• Ensure consistency among similar reviews
A Brief History of Combinations
8

9
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

➢ PMOA = Primary Mode of Action; originally not
defined in statute, but in regulations.
– Final Rule – 8/25/2005; 70 Fed. Reg. 49848
– Cures Act (2016) – added statutory definition into Section 503(g)
of Act
➢ Mode of Action: the means by which a product
achieves an intended therapeutic effect or action
21 CFR 3.2(k)
PMOA -- Determining Which Center Leads
1
0

➢ Primary mode of action -- 503(g)(1)(C) of Act
– “For purposes of this subsection, the term "primary mode of
action" means the single mode of action of a combination
product expected to make the greatest contribution to the
overall intended therapeutic effects of the combination
product.”
➢ Three types of modes of action:
– Biological product
– Device
– Drug
➢ Combination products typically have more than one
identifiable mode of action
Source: 21 CFR 3.2(m)
PMOA …
1
1

➢ 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.
Constituent Parts
1
2

➢ Proposed use(s) or indication(s)
➢ How it achieves its overall intended therapeutic effect(s)
– Cures Act clarification – 503(g)(1)(E) – “In determining the primary
mode of action of a combination product, the Secretary shall not
determine that the primary mode of action is that of a drug or
biological product solely because the combination product has any
chemical action within or on the human body.”
• Reason – a device might trigger chemical responses, but may not be used to
determine if that is not its primary intended purpose
➢ Relative contribution of each component toward the
overall intended therapeutic effect
➢ Duration of the contribution of each component towards
the intended therapeutic effect
➢ Data or information that describes and supports the mode
of action
Factors Impacting PMOA
1
3

➢ If unable to determine most important therapeutic
action with reasonable certainty, FDA will use the
“assignment algorithm” at 21 CFR 3.4(b).
➢ Two major factors, considered in order:
– 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 the most significant S&E questions
presented by the combination product?
The PMOA Decision Tree –
“Assignment Algorithm”
1
4

➢ Intended use/indication(s)
➢ Overall therapeutic effect(s)
➢ Does a device component incorporate a novel or
complex design or have potential for significant
failure modes?
➢ Is drug component a new molecular entity or
formulation?
➢ Has a generic version of drug been approved?
➢ Is biological component a particularly fragile
molecule?
Assignment Algorithm – Additional Factors
1
5

➢ How well understood are the components on a
comparable basis? Is one more risky?
➢ Which components raise greater risks?
➢ Have any components been approved/cleared?
➢ Is there a new indication, route of administration, or
significant change in dose or use of component?
Assignment Algorithm – Additional Factors
…
1
6

➢ Voluntary Formal Process under 21 CFR Part 3
➢ Seeks to determine:
– Regulatory Identity or Classification
– Assignment of Lead Center
– Collateral issue -- clarification of regulatory pathway
➢ If don’t seek RFD and submit for marketing, FDA
may stay review clock while making designation
determination
➢ Note – also can be used to get classification of a
single component product, where you are not sure if
drug, device, biologic …
Not Sure of PMOA --
Requests for Designations (RFD's)
1
7

➢ When to file RFD:
– Before filing any application for investigational or marketing
authorization
– As soon as enough info exists for FDA to make a decision
➢ Can meet with OCP before filing RFD -- not required
➢ Regulation – 21 CFR 3.7
➢ Guidance on How to Write a RFD
– Federal Register – Monday, April 18, 2011 – 76 Fed. Reg. 21752
– http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM
251544.pdf
➢ Format – follow descriptions in 21 CFR 3.7(c)(1)-(3)
➢ Electronic filing – allowed, but not required
➢ 15-page limit (with attachments)
RFD’s …
1
8

RFD Contents – 13 Sections
• Contact Information
• Product Name
• Description of Product
• Prior Approvals and
Agreements
• Chemical, Physical or
Biological Composition
• Development Work &
Testing
• Manufacturing Information
• Proposed use or Indications
• Modes of Action (all) and
Primary Mode of Action
• Schedule and Duration of
Use
• Dose and Route of
Administration
• Related Products
• Other Relevant Information
• Sponsor’s Recommendation
on PMOA/classification and
Center with jurisdiction
19

➢ Guidance – drills down on the 13 sections
➢ Some Key Points from the Guidance:
– State how you think your product should be assigned and why
• State the basis for your assertion why your selected PMOA is most
important therapeutic action for the product
• Assignment Algorithm -- if you cannot determine, “with reasonable
certainty,” the PMOA, must use assignment algorithm (Slides 12 - 14)
– Even if you are sure, should address anyway
– Appropriate to file an RFD even if you believe that the product
is NOT a combination product, but uncertainty remains
RFD’s …
2
0

➢ OCP reviews RFD’s for completeness w/in 5 work
days
➢ 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 calendar days; if not
YOUR recommendation wins!!
RFD’s – OCP Process
2
1

➢ Request for Reconsideration
– Submit within 15 calendar days
– Cannot exceed 5 pages in your reconsideration submission
– No new information (if you do, FDA will consider it a new
RFD)
– FDA response within 15 calendar 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)
RFD’s – Process …
2
2

The “Pre-RFD” Meeting/Request
Feb. 2018 Guidance – “How to Prepare a Pre-Request for Designation
(Pre-RFD)”
• Highly recommended –
– can submit at any time during
product development
– no limit on pages for submission
– not binding (good if you don’t like
the feedback)
– does include inter-Center
consultation
– then can follow with formal RFD
• FDA – written preliminary
classification or jurisdictional
assessment -- 60 calendar days
23
RFDvs.Pre-RFD
• Can also request in-person meeting (could be via phone), but timing factors
will vary

➢ September 2017 -- Classification of Products as Drugs
and Devices and Additional Product Classification
Issues -- https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM258957.pdf
– helpful guidance to appreciate differences between when a
product has a drug vs. device vs. biologic MOA
– reminds you that, particularly relative to devices, to be a medical
device the “primary intended purpose” must not be chemical
or metabolic activity.
• THUS, if a product does generate some chemical activity, but (a) that
chemical activity does not constitute the “primary intended purpose” and
(b) the product otherwise meets the definition of a device, it IS a device
even though it has some chemical activity.
• See also, Section 503(g)(1)(E), discussed at Slide 13
Other Jurisdictional/Classification Actions

➢ May 15, 2018 -- https://www.gpo.gov/fdsys/pkg/FR-2018-05-15/pdf/2018-10321.pdf
– FDA characterizes as basically cleaning up various issues in 21
CFR Part 3 to address various changes that have occurred in past
15 years or so due to FDASIA and the Cures Act
– Will substitute a total new version of Part 3
➢ Stay tuned … has gotten some adverse comments
Proposed Jurisdictional Rule
25

➢ Breath Test Combinations
– http://www.fda.gov/CombinationProducts/JurisdictionalInformation/JurisdictionalUpdates/ucm103134.htm
➢ Heparin Catheter Lock-Flush Solutions
– http://www.fda.gov/CombinationProducts/JurisdictionalInformation/JurisdictionalUpdates/ucm103161.htm
➢ Metered Dose Inhalers, Spacers and Other
Accessories
– http://www.fda.gov/CombinationProducts/JurisdictionalInformation/JurisdictionalUpdates/ucm10
3179.htm
Jurisdictional Decisions -- Examples
2
6

➢ January 22, 2013 – 78 Fed. Reg. 4307
• https://www.federalregister.gov/articles/2013/01/22/2013-
01068/current-good-manufacturing-practice-requirements-for-
combination-products
➢ FDA: “The final rule is largely identical to the
proposed rule.” 78 Fed. Reg. @ 4308.
➢ Creates 21 CFR Part 4
➢ Effective date: 180 days after promulgation – July 22,
2013
➢ Guidance Document – January 2017 – deep drill down
Final Rules on GMPs
2
7

➢ Assumptions underlying final GMP rule:
– During and after components combined, both sets of cGMP
regulations apply (whether a single entity product or co-packaged
products)
– However, compliance with both sets of regulations can generally
be achieved by using either regulation and agency does not see
need for parallel systems
➢ Two options under final rule
– Parallel systems -- satisfy all requirements for both systems
– “Streamlined Approach” – full compliance with one system,
plus compliance with designated parts of other system [where
other system is not your usual system] IS full compliance with all
of second system
GMPs …
2
8

➢ Must meet all drug GMP rules, plus these device
Quality System rules:
– 820.20 – Management Responsibility
– 820.30 – Design Controls
– 820.50 – Purchasing Controls
– 820.100 – Corrective and Preventive Action (CAPA)
– 820.170 – Installation
– 820.200 – Servicing
• 21 CFR 4.4(b)(1)
Streamlined – Drug "Dominant"
2
9

➢ Must meet all device Quality System rules, plus these
drug GMP rules:
– 211.84 – Testing and approval or rejection of components, drug
product containers, and closures
– 211.103 – Calculation of yield
– 211.132 – Tamper-evident packaging for OTC drugs
– 211.137 – Expiration dating
– 211.165 – Testing and release for distribution
– 211.166 – Stability testing
– 211.167 – Special testing requirements
– 211.170 – Reserve Samples
• 21 CFR 4.4(b)(2)
Streamlined – Device "Dominant"
3
0

➢ June 13, 2018 – 83 Fed. Reg. 27609
➢ Includes a list of acceptable alternative approaches for certain
aspects of streamlined GMP compliance
– very technical drill down; will not review in detail here
➢ Drug issues addressed:
– 211.165 – Testing & Release for Distribution
– 211.166 – Stability Testing
– 211.167 – Special Testing Requirements
– 211.170 – Reserve Samples
➢ Device issues addressed
– 820.30 – Design Controls
– GMP exempt devices – are exempt for the device component of a
combination product
➢ Discusses how to interact with FDA if you have GMP concerns
on combination products.
Notice on Alternative GMP Approaches
31

➢ What governs in investigational stage?
– Phase 1 – drug component exempt from drug GMPs
– Device component – exempt, except design controls in all phases
➢ Does it apply to already approved combination
products?
– Yes; the rule does not change what applies, but creates a system
for understanding how to apply the distinct GMP rules
➢ Defined “convenience kits” –
“ … only kits that solely include products that are: (1) Also legally marketed
independently and (2) included in the kit as already packaged and with the same
labeling as for independent marketing.
GMPs – Issues Addressed in Final Rule
3
2

➢ What if two provisions (QSR v. Drug GMP) appear to
clash?
– follow the one more “specifically applicable to the constituent
part” (if you can figure that out) – 78 Fed. Reg. at 4314
➢ What happens while a constituent part is being made
at a separate facility?
– all CGMP provisions applicable to that constituent part (i.e.,
drug, device, or biologic) must be satisfied at that facility
• and … when it is brought to another facility where it is combined with a
different constituent part, then you have to meet the CGMPs that apply to
both …
• but … you can use the “streamlined” approach
3
3

➢ Design controls –
– to be addressed in guidance
– “The design history file for a combination product … must
address all design issues resulting from the combination of
the constituent parts, regardless of whether” the
manufacturer picks a “drug dominant” or “device dominant”
scheme (or full implementation of both) – 78 Fed. Reg. 4315
– Examples:
• document and provide objective evidence that the drug is appropriate for
use with the device – e.g., why a particular drug will work with a drug-
eluting stent
• document that the device is appropriate for the drug -- e.g., that a syringe
will not interact with the drug
3
4

➢ Blood and blood component products – also must
meet requirements of 21 CFR Part 606
➢ Human Cellular and Tissue-based Products
(HCT/Ps) – Current Good Tissue Practices apply if
product is also regulated as a drug, device or biologic
– Section 361 of Public Health Service Act – if HCT/P is
combined with another article (other than water and certain other
agents), it is a drug, device or biologic
– 21 CFR 1271 will apply if the HCT/P is also part of a
combination product, especially the Good Tissue Practice rules at
21 CFR 1271.145 et seq.
GMPs -- Special Cases
3
5

➢ Final Rule -- Federal Register, Dec. 20, 2016
– https://www.gpo.gov/fdsys/pkg/FR-2016-12-20/pdf/2016-
30485.pdf
➢ Basic approach
– Generally will follow the reporting system applicable to the type
of marketing application under which cleared (if single
application) -- NDA/PMA or 510(k)/BLA
– Assumption – the systems are “substantially similar”
– But, there are seven types of safety reports that are unique – have
to see if one applies, in your scenario, to your combination
product
Post-Marketing Safety Reporting
3
6

➢ 5-Day Report – under Medical Device Reporting (MDR) Rule –
when you learn of a reportable event associated with the device that
necessitates remedial action to “prevent an unreasonable risk of
substantial harm” to public health
➢ 30-Day Device Malfunction Report – under MDR, get info that
“reasonably suggests” the device has malfunctioned and, if
malfunction were to recur, the device or a similar device you market
would be likely to cause or contribute to death or serious injury
➢ Part 806 – Reports of Corrections – have 10 working days from
initiating a correction or removal subject to Part 806 (i.e., a Class I or
II recalls; Class III recalls are not subject to 806)
The Seven Unique Safety Reports
3
7

➢ 15-Day Alert – for drugs and biologics – reports of a serious and
unexpected adverse event
– Note: under MDR, “serious” events are reportable in 30 days, but MDR does
not talk about unexpected, so 15-day Alert governs where a combination
product containing a device has a serious and unexpected event if you can’t
determine which component caused the AE
➢ 3-Day Field Alert – for drugs only under 21 CFR 314.81(b)(1) – certain
types of problems with drugs such as: bacteriological contamination,
failure to meet specifications (e.g., stability) or labeling errors that could
lead to product mix-ups
➢ Expedited Blood Fatality Report – if blood collection or transfusion is
fatal, has to be reported in 7 days of the fatality
➢ Biological Product Deviation Reports – 21 CFR 606.171 – 45 days
from when you discover a GMP or other deviations that can affect safety,
purity, or potency
The Magnificent Seven …
3
8

➢ If a single application covers the combination:
– Use reporting rules required under the particular application
– As applicable under factual scenario, use one of Seven Types
➢ When two applications cover the combination:
– If you can reasonably conclude which component caused the
adverse event, you can use that component’s reporting system
– If unclear which component caused AE, have to satisfy reporting
requirement of all types of application
– If other application is held by a third party, have to notify that
person within 5 days of learning of event and also satisfy your
reporting duties
The Safety Rule in Action
3
9

➢ Compliance Policy – “immediately in effect”
– FDA delays effective dates of five provisions of 12/16 Final Rule
to allow applicants to update systems and procedures
– Affected
• 4.102(c) – combination applicants where product has a drug component
• 4.102(d) – “other reporting requirements”
• 4.104(b)(1) – where to submit a drug report
• 4.104(b)(2) – where to submit a device report
• 4.105(b) – record retention lengths
– Delayed effective dates:
• July 31, 2019 – if you use FAERS or eMDR
• January 31, 2020 – if you use VAERS
March 2018 PSMR/AE Guidances
40

➢ Draft Guidance – “Postmarketing Safety Reporting
for Combination Products”
➢ This draft guidance is a deep drill down of the Final
Rule – won’t discuss here as not in effect yet
March 2018 PSMR/AE Guidances …
41

➢ Concept Paper on Marketing Applications for
Combination Products
– http://www.fda.gov/downloads/CombinationProducts/RequestsforComment/UCM108197.pdf
➢ Basics:
– PMOA does not ensure application status; but lead Center
– Single application usually is sufficient and, per Cures Act, FDA is
to use a single app. “whenever appropriate” – 503(g)(1)(B)
– 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?
4
2

➢ 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
How Many Applications?...
4
3

➢ Guidance on User Fees for Combination Products –
April 2005
– http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM147118.pdf
➢ Basics
– Depends on type and # of applications
– If two applications submitted voluntarily, pay two fees
– If two applications REQUIRED, still pay two fees
➢ “Innovative Product Waiver” – consider seeking
User Fees – Can I Pay the Least Amount?
4
4

➢ Combination Products Main Homepage
– http://www.fda.gov/CombinationProducts/default.htm
➢ Frequently Asked Questions on Combination
Products
– http://www.fda.gov/CombinationProducts/AboutCombinationProducts/ucm101496.htm
➢ Jurisdictional Determinations –
– http://www.fda.gov/CombinationProducts/JurisdictionalInformation/RFDJurisdictionalDecisions/default.htm
➢ Final Rule on “Primary Mode of Action” –
8/25/2005; 70 Fed. Reg. 49848
– https://www.gpo.gov/fdsys/pkg/FR-2005-08-25/pdf/05-16527.pdf
➢ SMG 4011 – Inter-Center Consultative/Collaborative
Review Process
– http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/StaffManualGuides/UCM283569.pdf
References
4
5

Category Title Type Date
Post-market Postmarketing Safety Reporting for Combination Products Draft 3/2018
Post-market Compliance Policy for Combination Product Postmarketing Safety Reporting Final 3/2018
Jurisdictional How to Prepare a Pre-Request for Designation (Pre-RFD) Final 02/2018
Jurisdictional Classification of Products as Drugs and Devices and Additional Product Classification Issues Final 09/2017
Post-market Current Good Manufacturing Practice Requirements for Combination Products(PDF - 336KB) Final 01/2017
Pre-market
Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and
Development(PDF - 336KB)
Draft 02/2016
Pre-market
Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with Drugs and Biological
Products (PDF - 153KB)
Final 06/2013
Pre-market
Glass Syringes for Delivering Drug and Biological Products: Technical Information to Supplement
International Organization for Standardization (ISO) Standard 11040-4
Draft 04/2013
Post-market
Submissions for Postapproval Modifications to a Combination Product Approved Under a BLA, NDA, or
PMA (PDF - 101KB)
Draft 01/2013
Jurisdictional
Interpretation of the Term "Chemical Action" in the Definition of Device Under Section 201(h) of the
Federal Food, Drug, and Cosmetic Act
Draft 06/2011
Jurisdictional How to Write a Request for Designation (RFD) Final 04/2011
Pre-market
New Contrast Imaging Indication Considerations for Devices and Approved Drug and Biological Products
(PDF - 159KB)
Final 12/2009
Jurisdictional Devices Used to Process Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Final 07/2007
Pre-market Early Development Considerations for Innovative Combination Products Final 09/2006
Pre-market Application User Fees for Combination Products Final 04/2005
Pre-market
Submission and Resolution of Formal Disputes Regarding the Timeliness of Premarket Review of a
Combination Product
Final 05/2004
FDA List of Combination Prod. Guidances
46

47
OVER-THE-COUNTER
-- “OTC” -- DRUGS

➢ OTC Review – monograph system
– By regulation, FDA makes a “GRASE” determination – thus, not
a “new drug”
– Covers bulk of marketed OTCs
– Lacks exclusivity
➢ Rx – OTC Switches
– May enjoy patent protection
– May enjoy Waxman-Hatch Exclusivity
• Yes – most
• No -- Minoxidil
➢ Direct-to-OTC
– Very, very rare
– Only ones I know are both local –
• Avanir’s Abreva®;
• SalonPas® -- Hisamatsu
OTC’s – Three Routes

Why Switch?
➢ Preserve franchise in face of impending generic
competition on the Rx
➢ Boost sales
➢ Downside
– Usually not reimbursed by insurance

OTC’s – Key Issues
➢ Wellpoint Petition – sought to “force” Claritin OTC
➢ Will FDA file its own petitions?
➢ T.E.A. Rule – foreign data can now be used to
support an OTC Switch
➢ What studies are sufficient to support Waxman-Hatch
Exclusivity?
– Make sure they’re essential – Minoxidil
– More than one similar product can get exclusivity

➢ Tamper-resistant packaging – required by 21 CFR
211.132 – for OTC drugs (except topicals, dentrifices,
insulin, and throat lozenges)
➢ Can’t be an Rx and an OTC (per FDA) – but, see Miralax
generics challenge
➢ Adverse events
– PL 109-462, the Dietary Supplement and Nonprescription
Drug Consumer Protection Act, December 2006
– Serious adverse events must be reported by person listed on label
– Draft guidance – 2007 – for those OTCs not under an A/NDA
Other OTC Drug Requirements
51

OTC Drug Labeling
52
• Standardizedto“DrugFacts”–21CFR201.166

Reforming the System
• Legislation – Over-the-Counter Monograph Safety,
Innovation, and Reform Act of 2018
– HR 5333 -- (passed House on July 16)
– S. 2315 – approved by committee
• FDA views
– Woodcock testimony before Congress – Sept. 2017
– Gottlieb statement – July 2018
– Draft guidance -- Innovative Approaches for
Nonprescription Drug Products

Orphan Drugs

➢ Enacted – 1983
➢ Goal -- create incentives for pharmaceutical companies to
adopt "orphan" drugs for uses for rare disorders.
➢ “Orphan" -- many drugs were known as potentially
effective for rare diseases, but had been orphaned --
abandoned for developmental purposes -- by the
pharmaceutical industry due lack of profitability associated
with small patient population (aka “buyers”)
ADOPTING ORPHANS –
The Orphan Drug Act

➢ Orphan Drug Act -- created four key incentives to
facilitate drug development for rare diseases:
– Seven years marketing exclusivity during which time no other
company can secure approval for the same drug for the orphan
indication
– Protocol assistance
– Tax credits
– Research Grants
Orphans . . .

➢ To qualify for benefits under the Orphan Drug Act, a
drug must serve a patient population:
– < 200,000 people in the United States or
– if > 200,000, orphan drug applicant must show it cannot
reasonably recoup its commercial investment in the research and
development of the product –
• rarely used
➢ Key question for orphan drug status is patient
population --
– the indication sought must be “medically plausible”
– not just a "salami sliced" indication of a greater patient
population that might be otherwise over 200,000.
How Does a Drug Become an
Adoptable Orphan?

➢ To get orphan drug benefits, a sponsor must apply for
orphan drug designation.
➢ Process -- sponsor-specific
➢ 21 CFR 316.20 requires that, among other things, the
sponsor show:
– patient population proposed -- less than 200,000 people per year.
– is a confidential process with the designation application not
being one subject to public disclosure until after it is approved, if
it is approved.
➢ Once approved, the designation will appear in a
quarterly cumulative list that the Agency publishes
and makes available on its website.
➢ Several guidances available
Orphan Designation

Designation Issues – or Can Identical Drugs
Be Adopted by Two Different Families – or
does one Drug have to be Superior?
➢ Clinical Superiority – FDA may regard – for Orphan Drug
Act purposes, including exclusivity -- as different, drugs that
are chemically the same and for same indication if the second
drug is clinically superior to the first drug
– prior to 2017’s Food & Drug Administration Reauthorization Act
(FDARA), FDA had construed the ODA that you had to show
superiority
– BUT, a 2014 court case – Depomed (re Gralise®) had found that
superiority was not required – in effect, you could have two drugs with
O.D. exclusivity
• FDA – after Depomed, said it would ignore the court’s decision
– FDARA resolved this for drugs subject to the ODA after the
enactment date of FDARA (August 18, 2017)

➢ 3 Types of Clinical Superiority – each must show that
it presents a “significant therapeutic advantage” as to
either:
– Greater Efficacy; or
– Greater Safety; or
– Providing a Major Contribution to Patient Care (“MC-PC”)
➢ How to Prove Superiority – 21 CFR 316
– Effectiveness – “as assessed by effect on a clinically meaningful
endpoint in adequate and well controlled trials”
• typically – direct, head-to-head, clinical trials (as per a comparative claim)
– Safety – “in a substantial portion of the target population”
Clinical Superiority
60

➢ Very subjective; some factors FDA will consider (from
2013 revised regulations);
– Convenient treatment location (e.g., home vs. clinic)
– Reduced treatment burden
– Increased patient comfort
– Improved administration
– Potential for self-administration
➢ Not MC-PC:
– Increased quality of life
– Improved patient compliance
How to Prove MC-PC Superiority

➢ Efficacy
– Serono’s Rebif >to Avonex for relapsing-remitting MS based on a
head-to-head clinical study (2002)
➢ Safety
– Biogen’s Avonex > Berlex’s Betaseron due to a reduced risk of an
adverse event – injection site necrosis
➢ MC-PC
– Academic’s Sotalol HCl > Betapace due to change in dosage form
from oral to injectable allowed use with patients that could not use oral
dosage
– Eagle’s Ryanodex > Dantrium IV because anesthesiologist could
prepare in 1 minute vs. 1 hour for Dantrium, allowing anesthesiologist
to concentrate on treating the patient
Clinical Superiority (“>”) – Examples
62

➢ FDA Final Rule – July 2013 – situations where a viable
orphan subset may exist in a “non-rare” disease
– Toxicity of the drug – e.g., a small subset are refractory to normal
treatment, but would respond to a more toxic drug
– Mechanism of action – e.g., breast cancer is not rare, but those
where the drug mechanism impacts a specific biomarker where
the population is orphan
➢ Illegitimate slicing
– Disease grade – e.g., all breast cancer stages are seen as same
disease; but contrast – FDA says pneumonia in CF patients is
different disease than community-acquired pneumonia
– Clinical trial – inclusion/exclusion criteria – can’t pick only “left-
handed lawyers”
Subsets – Legitimate “Salami Slicing”

➢ “Molecular differentiation” (my term) -- in other cases,
FDA has gone to some length to differentiate a product on
the basis of how its molecular structure differs from an
approved orphan drug.
– “Silly Little Amino Acid” Case – 91 vs. 92 amino acid chains
“Same” Drug?
64

Orphan Drug Exclusivity
➢ Protects the orphan drug for the orphan indication
➢ 7 years
➢ Good thing – can’t “remake wheel” (distinguish
Waxman-Hatch exclusivity which does not bar a full
NDA for a drug with W-H exclusivity)
➢ Beware – less incentive to study approved drugs for
orphan uses – generics may come in and be used off-
label

➢ Only helpful to a company that is actually enjoying
taxable income that needs to be offset.
➢ For startups, this may not occur any time in the short
term when the needs of the tax cut might be most
useful.
➢ See a tax professional -- may be able to give you more
advice as to whether any losses can be carried forward
and for how long so as to be able to take advantage of
the tax cut provisions
➢ Most observers -- low utility
Tax Credits

Protocol Assistance
➢ Orphan Drug sponsors are as eligible for significant
additional assistance from FDA in the design of its
clinical study protocols (caveat: nature of that aid
is not stated very clearly anywhere)
➢ LINK any assistance to a clear written agreement
with the Agency as to the nature of the clinical
studies to be performed

Research Grants
➢ Awarded by FDA to qualified applicants pursuant to
criteria being articulated by the Agency.
➢ While the grants can be somewhat substantial, they
are dependent upon the Agency receiving
appropriate funding by Congress for the grants.
➢ Fairly constant struggle for FDA -- historically the
gross amount of grants available in a single year
rarely exceeds $2 million and individual grants
normally range from $50,000 to $200,000.
➢ Qualifying for a grant involves a number of hurdles

➢ Commissioner Blog -- June 29, 2017 – Announced --
Goals & Features
– Eliminate backlog within 90 days
– 100% of new O.D. Designation requests to get response in 90 days
– Webinar Tutorial on Designation Requests
• access at:
https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanP
roductDesignation/ucm597126.htm
– Plan – access at:
• https://www.fda.gov/downloads/ForIndustry/DevelopingProductsforRareDiseasesConditions/Howtoapply
forOrphanProductDesignation/UCM565068.pdf
➢ Draft Guidance – Dec. 2017 -- Designation for Pediatric
Subpopulations of Common Diseases
FDA O.D. Modernization Plan
69

➢ O.D. Designation Pilot Plan – fillable designation form
➢ Public workshop – held on May 9, 2018 -- to address
changing landscape of O.D. development posed by
targeted therapies and molecularly defined diseases.
– https://www.fda.gov/NewsEvents/MeetingsConferencesWorkshops/ucm592778.htm
➢ MOU with NORD -- for collaboration to enhance
patient involvement in regulatory discussions
➢ More at:
https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/Events/u
cm593077.htm
FDA – 2018 Rare Disease Day Announcements
70

➢ No difference in standards for approval – still must
prove “substantial evidence” of safety and
effectiveness using adequate and well-controlled
investigations and clinical benefit
➢ Clinical study hurdles
– Small patient populations
• Hard to recruit
• Clinical investigators – more likely to be “naïve” as to Good Clinical
Practices (GCP)
– Poorly understood disease processes
– Many orphan diseases are genetically based – estimated as high as
80% -- thus, can be very heterogeneous populations –
confounding study predictability
Challenges in Orphan Drug Development
7
1

➢ Clinical study hurdles …
– Often chronic, progressive, serious, life-limiting and life-
threatening with unmet medical needs
– Endpoints, outcome measures, tools, instruments, biomarkers
usually lacking
– “Natural history” of diseases simply not as well documented
➢ Clinical study differences – examples:
– Carglumic acid – for NAGS deficiency – approved with just one
study – an open label, historically controlled, retrospective cases
series of 23 subjects
– Dalfampiridine – to improve walking in patients with multiple
sclerosis – two randomized, placebo controlled studies with 540
subjects
Orphan Drug Development Challenges …
7
2

➢ Tougher to recruit for many reasons
– Less of them
– Ethical considerations
• Informed consent/assent
• Willingness of parent or guardian
– Organ development differences – not just proportionally smaller
adults
– High genetic involvement
Clinical Challenges – Rare Pediatric Diseases

Statistics – A Very Successful Law
74

75
Source: “Insights into Rare Disease Drug Approval: Trends and Recent Developments.” Lanthier, Mike (Operations Research Analyst, FDA
Office of Commissioner). NORD Rare Diseases & Orphan Products Breakthrough Summit. October 17, 2017. at Slide 4.

Source: Lanthier, at Slide 7.

aaaa
aaaa

2017 O.D. Approvals – Therapeutic Areas

Time to Market
81

82
Source: https://csdd.tufts.edu/csddnews/

Questions?
➢ Call, e-mail or write:
Michael A. Swit, Esq.
San Diego, California 92130
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 a leading developer of diagnostics and research tools. 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.

Combination Products, Orphan Drugs, and OTC Drugs

Empfohlen

Empfohlen

Weitere ähnliche Inhalte

Was ist angesagt?

Was ist angesagt? (20)

Ähnlich wie Combination Products, Orphan Drugs, and OTC Drugs

Ähnlich wie Combination Products, Orphan Drugs, and OTC Drugs (20)

Mehr von Michael Swit

Mehr von Michael Swit (20)

Kürzlich hochgeladen

Kürzlich hochgeladen (20)

Combination Products, Orphan Drugs, and OTC Drugs