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Cross Labeling Combination Products

Bradley Merrill Thompson, MBA, JD, RACEpstein Becker & Green PC

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One way to make sure crime doesn't pay would be to let the

government run it.Ronald Reagan

CPC’s Proposed Approach:The cross labeling issue can be addressed

under current regulations

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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

Potential impact on their product’s safety-effectiveness 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

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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 ActSome 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 togetherMandate that a manufacturer seek approval for

new uses of its productAssociation of American Physicians and

Surgeons, Inc. v. FDAForce manufacturers to “mutually conform”

their labeling to include new usesOpen or reference proprietary information in a

drug sponsor’s file for another sponsor seeking approval of a combination productExcept: 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 waiversExpedited review and

approval timesPower 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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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?

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?

Does the device IFU imply such a difference?

Yes

No

No

Yes

Yes

Flow Chart for Determining Whether Drug and Device Represent Cross Labeled Combination

Products Labeled as Such

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Does the nature of the device,regardless of its IFU, require

such a difference?

Are those differences or reasons significantenough, as shown through a risk

assessment, that the drug labeling should bechanged to assure safe and effective use of

the drug?

No

Cross LabeledCombination Product

requiring Cross-Labelingof drug and device

Not a Combination Productand No Specific Cross

Reference

Are there any other reasons whyapproval/clearance of the device

would requirea change to the drug labeling

No

No

Yes

Yes

No

Yes

Not a Combination Productbut Includes a Reference to"use only with" a specific

brand drug

Kit CombinationProduct with no change

to drug labeling

Can the safe and effectiveuse of the combination be

addressed through thedevice or kit labeling and

co-packaging withoutrequiring a change in the

drug labeling?

No Yes

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Not a Combo Product and No Specific

Cross Reference

Not a Combo Product But Includes Specific Reference

Cross Labeled Combo Product

Is an agreement

between the parties

assuring coordination required to approve the

device?

No 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.

Yes, an agreement

between the two companies is

required

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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 cross-reference 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.