Transcript Slide 1

Cross Labeling
Combination Products
Bradley Merrill Thompson, MBA, JD, RAC
Epstein Becker & Green PC
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CPC’s Proposed Approach:
The cross labeling issue can be addressed
under current regulations
One way to make sure crime
doesn't pay would be to let the
government run it.
Ronald Reagan
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The answer requires greater precision
in the definition of a combo product
• Most of the questions disappear when
products are properly categorized into:
– Combination Products
– Nearly combination products, but not
– Not combination products
• We will show an algorithm for properly
classifying products
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Four Principles
1. FDA should not play matchmaker between
companies.
2. The economic incentives that are most likely to
lead to important public health breakthroughs
are outside of FDA’s control.
3. FDA must approve or disapprove the products
as companies propose them, based on the
evidence.
4. But FDA, importantly, does have flexibility
under the law to weigh the risks.
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Why Companies Don’t Always
Want to Collaborate
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 Potential impact on their
product’s safetyeffectiveness profile
 Intellectual property and
confidentiality concerns
 Conflicting business
strategies
 Resource priorities
 Costs
 Product liability issues
 Interest in competing
products (drugs or delivery
systems, for example)
 Existing partnerships
Why Companies Don’t Want to
Collaborate
 Control
 Risk of having someone else’s “issues” control your
resources
 Potential limits on flexibility
 Changes have greater impact
 Manufacturing and quality concerns
 Desire to develop and retain internal expertise
 Familiarity or lack of familiarity with a potential “partner”
or product
 Differing perceptions on market size and what constitutes
“success”
 Ex: A sizeable market to a small device company
may not appear as large to a major pharmaceutical
company
 Additional regulatory exposure
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FDA’s Authority
 FDA derives its authority from the
Food, Drug and Cosmetic Act
(“Act”).
 The Act gives FDA broad authority.
For example, FDA can:
 Promulgate regulations for
enforcement of the Act
 Some limitations
 Approve drugs and devices,
license biological products
 Regulate use of drugs,
biologics and devices, including
those used for investigational
purposes
 Require manufacturers to
include “adequate directions for
use” in labeling
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FDA’s Authority Limits
 FDA’s authority is not all-encompassing. For
instance, FDA does not have the authority to:
 Require that companies work together
 Mandate that a manufacturer seek approval
for new uses of its product
Association of American Physicians and
Surgeons, Inc. v. FDA
 Force manufacturers to “mutually conform”
their labeling to include new uses
 Open or reference proprietary information in
a drug sponsor’s file for another sponsor
seeking approval of a combination product
Except: 505(b)(2)
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Tools for Encouraging Collaboration
• FDA cannot require
companies to work together,
but FDA can encourage
companies to collaborate in a
way that leads to innovation.
 Existing tools include:
 User fee waivers
 Expedited review and
approval times
 Power of persuasion – “just
ask”—but don’t lean
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Return to the Categorization Question
• A proper determination of whether a
product is truly a combination product
answers many of FDA’s questions
• A risk assessment is a key determinant
of whether the product must be treated
as a combination product
• FDA has more flexibility when a product
is not a combination product
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Flow Chart for Determining Whether Drug and
Device Represent Cross Labeled Combination
Products Labeled as Such
No
Look at proposed device
labeling: does it, or does it
need to in order to be used
safely and effectively,
individually specify a brand of
drug (not just a generic type)
expressly or by clear
implication?
Yes
Does the device labeling expressly
state that the drug is to be used
for a different intended use,
dosage form, strength, route of
administration or dose than stated
in the drug labeling?
Yes
No
Does the device IFU imply
such a difference?
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Yes
No
Does the nature of the device,
regardless of its IFU, require
such a difference?
Are those differences or reasons significant
enough, as shown through a risk
assessment, that the drug labeling should be
changed to assure safe and effective use of
the drug?
Yes
No
Yes
Yes
Are there any other reasons why
approval/clearance of the device
would require
a change to the drug labeling
No
Can the safe and effective
use of the combination be
addressed through the
device or kit labeling and
co-packaging without
requiring a change in the
drug labeling?
No
No
Not a Combination Product
and No Specific Cross
Reference
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Not a Combination Product
but Includes a Reference to
"use only with" a specific
brand drug
Cross Labeled
Combination Product
requiring Cross-Labeling
of drug and device
Yes
Kit Combination
Product with no change
to drug labeling
Not a Combo
Product and
No Specific
Cross
Reference
Is an
agreement
between the
parties
assuring
coordination
required to
approve the
device?
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No
Not a Combo Product But
Includes Specific Reference
Maybe, depending on a risk assessment.
This risk assessment would consider:
(1)The likelihood that product A will be
changed in the future.
(2)The consequences of possible changes to
product A.
(3)The effectiveness of company B’s ability
to monitor product A for such changes.
(4)The ability of company B to effectively
label the combined use without the need to
relabel product A.
(5)Any other issues that bear on the ability
of company B to assure the safety and
effectiveness of the combined product
without the cooperation of company B.
Cross Labeled
Combo
Product
Yes, an agreement
between the two
companies is
required
Summary
• Can device B be used safely and effectively with
already-approved drug A if the labeling for device B
only includes a generic reference to the category of
products that contains drug A?
– If the answer is yes, the two products together are
not combination products, there does not need to
be any cooperation between the two
manufacturers, and device B may be approved
despite any lack of cooperation.
– If the answer is no because a specific crossreference to drug A by brand is necessary to
assure safety and effectiveness, we must ask a
second question:
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Summary
• Do the two companies need to cooperate to ensure that
the products can be used together safely and
effectively? For example, does company A need to
agree to change its labeling to permit the combined use
of the products?
– If the answer is yes, the product is a combination
product, and by definition cooperation between the
two companies is required for the agency to approve
device B.
– If the answer is no, the two products are not
combination products, and there does not need to be
cooperation between the two manufacturers, and
device B may be approved despite any lack of
cooperation.
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Bottom Line
• FDA can do the right thing under the
existing regulations
• At it’s heart, much of the problem is with
communication between companies
• Right now FDA has some other
important priorities for combination
products such as GMPs, post approval
modifications, and clinical trial
requirements.
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