Document ID: FDA-2015-N-1260-0001
Agency: fda
Document Type: Proposed Rule
Title: Fixed-Combination and Co-Packaged Drugs: Applications for Approval and Combinations of Active Ingredients Under Consideration for Inclusion in an Over-the-Counter Monograph
Posted Date: 2015-12-23T05:00Z

[Federal Register Volume 80, Number 246 (Wednesday, December 23, 2015)]
[Proposed Rules]
[Pages 79776-79795]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-32246]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 300, 330, and 610

[Docket No. FDA-2015-N-1260]

Fixed-Combination and Co-Packaged Drugs: Applications for 
Approval and Combinations of Active Ingredients Under Consideration for 
Inclusion in an Over-the-Counter Monograph

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
proposing to revise its regulations on prescription fixed-combination 
drugs to apply the regulations to both prescription and nonprescription 
fixed-combination and co-packaged drugs and combinations of active 
ingredients under consideration for inclusion in an over-the-counter 
(OTC) monograph. These products must meet specific evidentiary 
requirements for approval. The proposed revisions would harmonize the 
requirements for prescription and nonprescription products and make 
them consistent with long-standing Agency policy.

[[Page 79777]]

DATES: Submit either electronic or written comments on this proposed 
rule by March 22, 2016. Submit comments on information collection 
issues under the Paperwork Reduction Act of 1995 (the PRA) by January 
22, 2016 (see the ``Paperwork Reduction Act of 1995'' section of this 
document). See section IX of this document for the proposed effective 
date of a final rule based on this document.

ADDRESSES: You may submit comments by any of the following methods, 
except that comments on information collection issues under the PRA 
must be submitted to the Office of Information and Regulatory Affairs, 
Office of Management and Budget (OMB) (see the ``Paperwork Reduction 
act of 1995'' section of this document):

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
     Mail/Hand delivery/Courier (for paper submissions): 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Docket No. 
FDA-2015-N-1260 for this rulemaking. All comments received may be 
posted without change to http://www.regulations.gov, including any 
personal information provided. For additional information on submitting 
comments, see the ``Request for Comments'' heading of the SUPPLEMENTARY 
INFORMATION section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.regulations.gov and insert the 
docket number(s), found in brackets in the heading of this document, 
into the ``Search'' box and follow the prompts and/or go to the 
Division of Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, 
MD 20852.

FOR FURTHER INFORMATION CONTACT: Diana Pomeranz, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, rm. 6208, Silver Spring, MD 20993, 
diana.pomeranz@fda.hhs.gov, 240-402-4654; or Stephen Ripley, Center for 
Biologics Evaluation and Research, Food and Drug Administration, 10903 
New Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993, 
stephen.ripley@fda.hhs.gov, 240-402-7911.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
    Purpose of the Regulatory Action
    Summary of the Major Provisions of the Regulatory Action
    Costs and Benefits
II. Background
    A. Regulatory History
    B. Advantages and Disadvantages of Fixed-Combinations and Co-
Packaged Drugs
III. Description of the Proposed Rule
    A. Definitions (Proposed Sec.  300.50)
    B. Applicability of the Proposed Rule (Proposed Sec.  300.51)
    C. Requirements of the Proposed Rule (Proposed Sec.  300.53)
    D. Combining One or More Active Ingredients With a Natural-
Source Drug, a Waived Product, or a Combination Already Included in 
an OTC Monograph (Proposed Sec.  300.55)
    E. Waiver (Proposed Sec.  300.60)
    F. Revision of OTC Combination Drug Provision (Proposed Sec.  
330.10(a)(4)(iv))
    G. Changes to Regulations on Fixed-Combination Biological 
Products (Proposed Sec.  610.17)
IV. Legal Authority
V. Analysis of Impacts
    A. Introduction
    B. Summary of Benefits and Costs of the Proposed Rule
VI. Paperwork Reduction Act of 1995
VII. Environmental Impact
VIII. Federalism
IX. Proposed Effective Date
X. Request for Comments
XI. References

I. Executive Summary

Purpose of the Regulatory Action

    We are proposing to revise our existing regulations in subpart B of 
part 300 (21 CFR part 300) on prescription fixed-combination drugs and 
establish new provisions applicable to prescription and nonprescription 
fixed-combination and co-packaged drugs and combinations of active 
ingredients under consideration for inclusion in an OTC monograph. 
Although current regulations exist for prescription fixed-combination 
drugs (current Sec.  300.50 (21 CFR 300.50)) and combinations of active 
ingredients under consideration for inclusion in an OTC monograph 
(current Sec.  330.10(a)(4)(iv) (21 CFR 330.10(a)(4)(iv)), they use 
slightly different language to state the same requirements. In 
addition, current Sec.  300.50 does not mention co-packaged drugs even 
though the Agency's long-standing policy has been to apply the 
requirements to co-packaged drugs. The proposed revisions would 
harmonize the requirements for prescription and OTC products and make 
them consistent with long-standing Agency policy.
    Fixed-combination or co-packaged drugs are intended to provide 
greater effectiveness (either by having a greater effect for a single 
indication or by treating more than one indication) than either 
ingredient alone, or by having one active ingredient enhance the safety 
or effectiveness of another active ingredient. Under the Federal Food, 
Drug, and Cosmetic Act (the FD&C Act) and related regulations, FDA has 
the authority to require specific types of evidence demonstrating that 
prescription fixed-combination or co-packaged drugs and OTC ingredients 
used in combination provide enhanced safety or effectiveness and can be 
labeled as such. This proposed rule describes the requirements 
applicants must meet to demonstrate that their fixed-combination or co-
packaged drugs are safe and effective.
    Under section 502(a) of the FD&C Act (21 U.S.C. 352(a)), 
prescription and OTC drugs are deemed ``misbranded'' if their labeling 
is false or misleading ``in any particular.'' Section 201(n) of the 
FD&C Act (21 U.S.C. 321(n)) states that labeling is misleading if it 
fails to reveal facts that are material with respect to the 
consequences which may result not only from the use of the product as 
labeled but from the use of the product under such conditions of use as 
are customary or usual. Information on how each ingredient in a 
combination contributes to the effect of the combination is a fact 
``material'' to the consequences that may result from customary use of 
that product. Thus, it is within FDA's authority to require such 
testing as is necessary to establish the safety and effectiveness of 
ingredients used in combination.

Summary of the Major Provisions of the Regulatory Action

    The proposed rule would apply to both prescription and OTC fixed-
combination and co-packaged drugs that are subject to approval under a 
new drug application (NDA) under section 505 of the FD&C Act (21 U.S.C. 
355), or a biologics license application (BLA) under section 351 of the 
Public Health Service Act (PHS Act) (42 U.S.C. 262), and to 
combinations of active ingredients under consideration for inclusion in 
an OTC monograph in accordance with part 330. It does not apply to 
individual natural-source drugs, which are drugs derived from natural 
raw materials, even though those drugs may contain multiple ingredients 
derived from the same source.

[[Page 79778]]

    Proposed Sec.  300.53 sets forth the requirements for combinations 
of active ingredients under consideration for inclusion in an OTC 
monograph and prescription and OTC fixed-combination and co-packaged 
drugs. Under proposed Sec.  300.53, two or more active ingredients may 
be combined in a fixed-combination or co-packaged drug or included as a 
combination in an OTC monograph when two requirements are met.
    First, under proposed Sec.  300.53(a)(1), each active ingredient 
must make a contribution to the effect(s) of the combination, enhance 
the safety or effectiveness of an active ingredient, or minimize the 
potential for abuse of an active ingredient. Second, under proposed 
Sec.  300.53(a)(2), the dosage of each active ingredient (amount, 
frequency of administration, and duration of use) must be such that the 
combination is safe and effective and provides rational concurrent 
therapy.
    Under proposed Sec.  300.53(b)(1), applicants and ``interested 
persons'' (persons seeking a change in an OTC monograph) who seek 
approval of a combination must state the intended use of each active 
ingredient in the combination. This requirement ensures that the 
therapeutic purpose of all active ingredients, even those that might 
not be considered active ingredients in other contexts, is claimed.
    Under proposed Sec.  300.53(b)(2), applicants and interested 
persons must provide sufficient evidence to demonstrate that their 
products meet the requirements of Sec.  300.53(a), including evidence 
demonstrating the contribution of each active ingredient to the 
effect(s) of the combination. The amount and type of data and 
information needed may vary depending on a number of factors, including 
the therapeutic intent of the combination.
    Because there are some products for which it would be infeasible or 
medically unreasonable or unethical to meet the requirements of this 
proposed rule, proposed Sec.  300.60 would give FDA the authority to 
grant a waiver of some or all of the requirements of the proposed rule 
at the request of an applicant or interested person or on its own 
initiative. In addition, FDA may grant a waiver for products that 
contain a subset of the components contained in a natural-source drug 
or a product that has already received a waiver under the proposed 
rule. FDA may grant a waiver of any of the requirements of proposed 
Sec.  300.53 depending on the evidence submitted.

Costs and Benefits

    The Agency has determined that this proposed rule is not a 
significant regulatory action as defined by Executive Order 12866.

II. Background

    We are proposing to revise our existing regulations in subpart B of 
part 300 on prescription fixed-combination drugs and establish new 
provisions applicable to prescription and nonprescription fixed-
combination and co-packaged drugs and combinations of active 
ingredients under consideration for inclusion in an OTC monograph.
    The proposed rule would apply to fixed-combinations (two or more 
active ingredients are combined at a fixed dosage in a single dosage 
form) of drugs (Refs. 1 to 5),\1\ as well as to co-packaged drugs (two 
or more separate drugs in their final dosage forms that are intended to 
be used together for a common or related therapeutic purpose and that 
are contained in a single package or unit) and combinations of active 
ingredients not already described in an OTC monograph.\2\
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    \1\ For purposes of this proposed rule, we will use the term 
``drug'' to include all products that fall under the definition of 
``drug'' in section 201(g) of the FD&C Act, which includes 
biological products that meet that definition, but does not include 
products that meet the definition of ``device'' under the FD&C Act 
(21 U.S.C. 301, et seq.). We also consider dietary supplements that 
are combined into a single dosage form with, or co-packaged with, a 
drug to meet the definition of ``drug'' under section 201(g) of the 
FD&C Act. This proposed rule does not otherwise address nor affect 
FDA policy on dietary supplements.
    \2\ For ease of reference, the term ``combination'' is used 
throughout this preamble to refer to these types of products 
collectively.
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A. Regulatory History

    Current FDA regulations contain requirements applicable to fixed-
combination drugs. The provisions on ``fixed-combination prescription 
drugs for humans'' are set forth in Sec.  300.50. The requirements for 
fixed-combination drugs that are marketed without a prescription and 
that are included in the OTC Drug Review are described in Sec.  
330.10(a)(4)(iv).
1. Fixed-Combination Drugs
    In the Federal Register of February 18, 1971 (36 FR 3126), FDA 
issued a ``proposed statement'' on fixed-combination prescription 
drugs. In this document, we said that the proposed statement on fixed-
combination drugs was intended as amplification of the requirement that 
an NDA or antibiotic drug application for a fixed-combination drug must 
be supported by substantial evidence that each ingredient designated as 
active makes a contribution to the total effect that the drug 
combination is represented to have and purports to possess. The 
proposed statement was issued as a regulation and it represented the 
logical application of the statutory and regulatory requirements for 
demonstrating effectiveness to the special case of fixed-combination 
drug products. The proposed statement noted experts' agreement that a 
fixed-combination drug product must have an advantage to the patient 
over and above that obtained when one of the individual components is 
used in the usual safe and effective dose. In the Federal Register of 
October 15, 1971 (36 FR 20037), we adopted a revised statement on these 
drugs in the form of 21 CFR 3.86, which later became Sec.  300.50 (40 
FR 13494, March 27, 1975).
    Current Sec.  300.50 explains how the requirements for 
demonstrating the safety and effectiveness of a drug submitted under 
section 505(b)(1) or (2) of the FD&C Act and subject to FDA's 
implementing regulations in part 314 (21 CFR part 314) apply to 
prescription fixed-combination drugs. Under current Sec.  300.50(a), 
two or more drugs may be combined in a single dosage form when each 
component makes a contribution to the claimed effects and the dosage of 
each component (amount, frequency, duration) is such that the 
combination is safe and effective for a significant patient population 
requiring such concurrent therapy as defined in the labeling for the 
drug. ``Special cases'' of this general rule are when a component is 
added to enhance the safety or effectiveness of the principal active 
ingredient or to minimize the potential for abuse of the principal 
active ingredient.
2. Drug Efficacy Study Implementation Review of Fixed-Combination Drugs
    Paragraphs (b) and (c) of current Sec.  300.50 relate to Agency 
determinations about the effectiveness of drugs under the Drug Efficacy 
Study Implementation (DESI) review, which FDA initiated in response to 
the Kefauver-Harris Drug Amendments to the FD&C Act (Pub. L. 87-781). 
The Kefauver-Harris Drug Amendments required FDA to assess the 
effectiveness of drugs that the Agency had previously approved for 
safety under the FD&C Act between 1938 and 1962. When the fixed-
combination drug regulations in Sec.  300.50 were established in 1971 
(36 FR 20037), the DESI review was ongoing for many DESI drugs. A 
significant number of the drugs undergoing DESI review were fixed-
combination drugs. According to current Sec.  300.50(b), if a fixed-
combination drug that is the subject of an NDA approved before 1962

[[Page 79779]]

has not been recognized as effective by FDA based on the Agency's 
evaluation of the appropriate National Academy of Sciences-National 
Research Council (NAS-NRC) panel report,\3\ or if substantial evidence 
of its effectiveness has not otherwise been presented, changes in 
formulation, labeling, or dosage may be proposed, and any resulting 
formulation must meet the criteria in current Sec.  300.50(a). Under 
current Sec.  300.50(c), a fixed-combination prescription drug for 
humans is considered to be in compliance with Sec.  300.50 if FDA has 
determined the drug to be effective based on evaluation of an NAS-NRC 
report on the fixed-combination drug.
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    \3\ Under DESI, FDA contracted with NAS-NRC to make an initial 
evaluation of the effectiveness of over 3,400 products that were 
approved only for safety between 1938 and 1962. NAS-NRC created 
panels to review these drug products; the panels' reports were 
submitted to FDA, which reviewed and reevaluated the finding of each 
panel and published its findings in Federal Register notices.
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    Because most of the few, still-pending DESI proceedings are in 
advanced stages, we do not believe that it is necessary to maintain 
provisions in the fixed-combination drug regulations that address the 
DESI review. Therefore, current Sec.  300.50(b) and (c) are omitted 
from this proposed regulation. Under this proposed rule, the 
manufacturer of a DESI drug could still propose a change in 
formulation, labeling, or dosage to meet the requirements of this 
proposed rule, and any DESI proceeding that is still pending when the 
final rule publishes will be subject to the requirements of the final 
rule.
3. OTC Combination Drugs
    In FDA's consideration of OTC combinations under the OTC Drug 
Review, the Agency has applied a standard similar to Sec.  300.50(a) 
under Sec.  330.10(a)(4)(iv) in the development of OTC monographs. An 
OTC drug that combines two or more safe and effective active 
ingredients may be generally recognized as safe and effective (GRASE) 
when the following criteria are met: (1) Each active ingredient makes a 
contribution to the claimed effect(s); (2) combining the active 
ingredients does not decrease the safety or effectiveness of any of the 
individual active ingredients; and (3) the fixed-combination, when used 
in accordance with labeling that provides adequate directions for use 
and warnings against unsafe use, provides rational concurrent therapy 
for a significant proportion of the target population. Combinations of 
active ingredients described in an OTC drug monograph may be marketed 
without prior Agency approval. Those combinations that are not 
described in a proposed tentative final monograph (TFM) or OTC 
monograph must either be added to the applicable OTC monograph or be 
approved under the NDA or abbreviated new drug application (ANDA) 
provisions in section 505 of the FD&C Act before they may be marketed 
in the United States.
4. Requirements for Fixed Combination Drugs and OTC Combination Drugs
    Current Sec. Sec.  300.50 and 330.10(a)(4)(iv) are not identical. 
Section 330.10(a)(4)(iv) refers to combinations of ``active 
ingredients'' rather than ``components,'' the term used in the 
prescription fixed-combination drug regulations; however, we do not 
believe this is a substantive difference because we have interpreted 
``component'' in Sec.  300.50 to mean active ingredient. Section 
330.10(a)(4)(iv) specifically states that the combining of active 
ingredients must not decrease the safety or effectiveness of any 
individual active ingredient, whereas, Sec.  300.50 does not 
specifically address this point. A prescription fixed-combination drug 
must be ``safe and effective for a significant patient population 
requiring such concurrent therapy,'' (Sec.  300.50(a)), while an OTC 
combination of active ingredients must provide ``rational concurrent 
therapy for a significant proportion of the target population'' (Sec.  
330.10(a)(4)(iv)).
    In addition, unlike the prescription fixed-combination drug 
regulations, the OTC combination standard does not specifically refer 
to the addition of a component to enhance the safety or effectiveness, 
or minimize the potential for abuse, of the principal active 
ingredient. However, FDA's guidance document entitled ``General 
Guidelines for OTC Drug Combination Products'' (OTC combination 
guidance), issued in 1978 (available at http://www.fda.gov/Drugs under 
``Guidances (Drugs)''), states that an ingredient claimed to be a 
pharmacological adjuvant (i.e., to enhance or otherwise alter the 
effect of another active ingredient) will be considered an active 
ingredient and may be included as part of a combination only if it 
meets the requirements of Sec.  330.10(a)(4)(iv). Because of the 
similarities between Sec.  330.10(a)(4)(iv) and proposed Sec.  300.50, 
we believe that combinations currently described in TFMs (which will 
have been proposed under the requirements of Sec.  330.10(a)(4)(iv)) 
will meet the requirements of proposed Sec.  300.50, if this proposed 
rule is finalized prior to the TFMs.
    This proposed rule aims to create uniform requirements for 
prescription and nonprescription fixed-combination and co-packaged 
drugs and combinations under consideration for inclusion in an OTC 
monograph by incorporating the concepts described in the OTC 
combination guidance, as well as those set forth in current Sec.  
330.10(a)(4)(iv) with those described in current Sec.  300.50.

B. Advantages and Disadvantages of Fixed-Combinations and Co-Packaged 
Drugs

    Most approved drugs contain a single active ingredient \4\ that has 
been demonstrated to be safe and effective in treating a particular 
disease or condition. However, sometimes two or more active ingredients 
are combined to provide greater effectiveness (either as a greater 
effect for a single indication, such as pain, or by treating more than 
one indication such as pain and insomnia) than either ingredient alone, 
or to enhance the safety or effectiveness of one of the active 
ingredients. Although it is almost always possible to take the 
ingredients separately, the combination might be advantageous in one or 
more ways. For example, it might be more convenient for patients or 
might facilitate compliance with a prescribed regimen.
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    \4\ As defined in Sec.  210.3.(b)(7) (21 CFR 210.3(b)(7)) and 
section III.A of this proposed rule, ``active ingredient'' is any 
component that is intended to furnish pharmacological activity or 
other direct effect in the diagnosis, cure, mitigation, treatment, 
or prevention of disease, or to affect the structure or any function 
of the body of man or other animals. The term includes those 
components that may undergo chemical change during the manufacture 
of the drug product and be present in the drug product in a modified 
form intended to furnish the specified activity or effect.
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    Although fixed-combination drugs can provide convenience, 
therapeutic benefit, and even economic benefit to patients, they also 
have potential disadvantages. These include the lack of flexibility in 
adjusting the dosage of each active ingredient to an individual 
patient's needs, the related possibility of overexposure, or 
unnecessary exposure to a particular active ingredient.
    Co-packaged drugs raise similar concerns to those associated with 
fixed-combination drugs, including whether each product contributes to 
the effect of the combination, whether there is a particular patient 
population that requires or can benefit from such a combination, and 
whether the co-packaged drugs can be used together safely and 
effectively (i.e., the use of the products together does not raise new 
safety concerns or interfere with the effectiveness of any active 
ingredient). For example, a drug manufacturer might co-package a lipid-
lowering drug with

[[Page 79780]]

an antihypertensive drug because patients with high cholesterol often 
also have high blood pressure. In this case, there is an identifiable 
patient population that needs both drugs. Although there are existing 
data on the safety and effectiveness of these products individually, 
before approving their use in combination, FDA would want to be sure 
that they can be used together safely and that each does not interfere 
with the effectiveness of the other. It would also be possible for a 
monograph to allow the marketing of a co-packaged drug in which the 
individual drugs have been determined to be generally recognized as 
safe and effective and also meet the requirements of this proposed 
rule.\5\ Co-packaged day-night cough-cold products might, for example, 
be included in the monograph for OTC cough-cold drug products in Sec.  
341.40 (21 CFR 341.40), and the monograph could specify the appropriate 
labeling for the co-packaged drug, if needed.
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    \5\ An applicant or interested person may seek to modify a final 
OTC drug monograph to include a co-packaged drug through a citizen 
petition filed in accordance with 21 CFR 10.30, or, if applicable, 
through a time and extent application provided for in Sec.  330.14. 
Co-packaged OTC products not covered by a final monograph (or 
covered by a TFM pending issuance of a final monograph) or included 
in the OTC Drug Review would require NDA approval.
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    Co-packaged drugs might also pose certain concerns that differ from 
those of fixed-combination drugs. These include potential confusion 
regarding labeling and misuse, abuse, or diversion of one of the 
products. An example of possible misuse is the development of drug-
resistant organisms when a patient fails to properly take co-packaged 
anti-tuberculosis drugs. Labeling confusion could also occur where 
information on individual product labels is inconsistent with labeling 
for use of the co-packaged drugs together. Furthermore, there is 
concern that abuse or diversion of an active ingredient may be easier 
with a co-packaged drug than with a fixed-combination drug because the 
desired active ingredient does not need to be chemically separated from 
the combination. We believe that the requirements in proposed Sec.  
300.53 are sufficiently broad to encompass evaluation of these and 
similar concerns, and it is appropriate to apply the same requirements 
to co-packaged and fixed-combination drugs.

III. Description of the Proposed Rule

    We are proposing to revise our existing regulations on prescription 
fixed-combination drugs and establish new provisions applicable to 
prescription and nonprescription fixed-combination and co-packaged 
drugs approved under a new drug application and to combinations of 
active ingredients under consideration for inclusion in an OTC 
monograph, in subpart B of part 300, as discussed in this document. The 
following is a description of the proposed regulation.

A. Definitions (Proposed Sec.  300.50)

    In revised Sec.  300.50, we propose to define the following terms 
used in subpart B (entitled ``Combination Drugs'') of part 300:
1. Active Ingredient
    We propose to define ``active ingredient'' as having the meaning 
consistent with that used in Sec.  210.3(b)(7), namely: Any component 
that is intended to furnish pharmacological activity or other direct 
effect in the diagnosis, cure, mitigation, treatment, or prevention of 
disease, or to affect the structure or any function of the body of man 
or other animals. The term includes those components that may undergo 
chemical change in the manufacture of the drug product and be present 
in the drug product in a modified form intended to furnish the 
specified activity or effect (see Sec.  210.3(b)(7)). Whether an 
ingredient is active or not may depend on its function in the product 
(e.g., human serum albumin can be a therapeutic product or can be an 
excipient for a protein therapeutic). The term ``component'' in this 
definition is intended to mean ``any ingredient,'' and FDA has 
consistently interpreted it in this manner in the context of fixed-
combination drugs.\6\ We note, however, that the term ``active 
ingredient'' does not encompass adjuvants incorporated into a vaccine 
to enhance the antigenic response to the vaccine, since the adjuvant 
does not furnish independent pharmacological activity or other direct 
effect in the diagnosis, cure, mitigation, treatment, or prevention of 
disease. For combinations that include large molecules 
(macromolecules), each individual molecular entity would generally be 
considered one active ingredient. In other words, a single active 
ingredient may consist of one macromolecule made up of two or more 
different chemical entities that are covalently linked. Even if each 
chemical entity has a distinct activity, such macromolecules would 
usually be considered a single active ingredient because the covalent 
bond generally renders the chemical entities inseparable. Naturally 
derived mixtures are usually considered to contain a single active 
ingredient because they generally include components whose contribution 
to the activity of the active ingredient is not known. For the purpose 
of fixed-combination biological product requirements, a single 
molecular entity is generally considered one active ingredient.
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    \6\ See 36 FR 3126, Feb. 18, 1971 (this statement is intended as 
amplification of the requirement that ``a new drug . . . application 
for a combination drug may be refused unless there is substantial 
evidence that each component designated as active makes a 
contribution to the total effect which the drug combination is 
represented to have and purports to possess'').
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    FDA also has long interpreted the term ``other direct effect'' in 
the definition of ``active ingredient'' to include nutritional effects 
of dietary supplements. When used as part of a fixed-combination or co-
packaged drug, dietary supplements are considered to be an active 
ingredient in that product and subject to the requirements of this 
proposed rule. See footnote 1 for additional discussion of the 
treatment of dietary supplements as drugs when used in combination with 
a drug.
2. Applicant
    We proposed to define ``applicant'' as any person who, to obtain 
approval of a fixed-combination or co-packaged drug, submits an NDA 
under section 505 of the FD&C Act or a BLA under section 351 of the PHS 
Act.
3. Botanical Raw Material
    We propose to define ``botanical raw material'' as a fresh or 
physically processed material derived from a single part of a single 
species of plant,\7\ or a fresh or physically processed alga or 
macroscopic fungus that has not been genetically modified using 
recombinant DNA technology or any other process that deliberately 
changes the genome. Examples of traditional medicines derived from a 
single part of a single species of plant are isatis leaf (Isatis 
indigotica Fort.), used in traditional Chinese medicine to treat 
diseases with high fever and skin eruptions, tanghen root (Codonopsis 
pilosula (Franch.) Nannf.), used to treat diabetes; and Rauwolfia 
serpentine for the treatment of hypertension.
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    \7\ If the plant from which the botanical raw material is 
derived is microscopic, the entire plant may be used and would be 
considered one part.
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    We encourage the study and development of botanical substances as 
botanical drug products. In 2004, we issued guidance for industry, 
``Botanical Drug Products,'' on conducting clinical studies of and 
submitting marketing applications for such products (69 FR 32359, June 
9, 2004). The guidance is available on the Internet at http://www.fda.gov/Drugs under ``Guidances

[[Page 79781]]

(Drugs).'' Using the principles explained in this guidance, we approved 
sinecatechin in 2006 and crofelemer in 2012, both of which are 
botanical new drugs.
4. Co-Packaged Drug
    We propose to define ``co-packaged drug'' as a product that 
contains two or more separate drugs in their final dosage forms that 
are intended to be used together for a common or related therapeutic 
purpose and that are contained in a single package or unit.
    Co-packaging two or more drugs might involve, for example, putting 
these products into the same blister pack, carton, or box, or in 
separate boxes that are shrink-wrapped together. Some co-packaged drugs 
have separate labeling for each of the individual products; whereas, 
other co-packaged drugs have joint labeling. For example, co-packaged 
Sodium Nitrite Injection and Sodium Thiosulfate Injection (Nithiodote) 
are marketed for the sequential treatment of acute cyanide poisoning 
that is judged to be life-threatening. When sodium thiosulfate is sold 
as a single entity, it is labeled for sequential use with sodium 
nitrite for treatment of acute cyanide poisoning that is judged to be 
life-threatening. When sodium thiosulfate is co-packaged with sodium 
thiosulfate, it is singly labeled for treatment of acute cyanide 
poisoning that is judged to be life-threatening. The Monistat 3 
Combination Pack for treatment of vaginal yeast infection is an example 
of a co-packaged OTC product the individual components of which are 
also sold individually (cool wipes, miconazole nitrate vaginal inserts, 
and miconazole nitrate cream). Miconazole nitrate vaginal inserts are 
sold separately as Monistat outside of a combination pack and are 
labeled for treatment of vaginal yeast infections. Similarly, 
miconazole nitrate cream is sold individually for treatment of vaginal 
itching. However, when these products are packaged together in the 
Monistat 3 Combination Pack, the co-packaged drug has one label for 
both products.
    In recent years, we have reviewed and approved several applications 
to market co-packaged drugs. Examples include Pravigard PAC (co-
packaged pravastatin sodium tablets and buffered aspirin tablets) for 
reducing the occurrence of serious cardiovascular and cerebrovascular 
events; co-packaged peginterferon alfa-2a and ribavirin for the 
treatment of hepatitis C; and co-packaged bismuth subsalicylate 
(gastrointestinal agent), metronidazole (antiprotozoal and 
antibacterial agent), and tetracycline hydrochloride (antibiotic) for 
the treatment of patients with active duodenal ulcer associated with 
Helicobacter pylori infection. Because our fixed-combination drug 
regulations in current Sec. Sec.  300.50 and 330.10(a)(4)(iv) do not 
specifically address the approval of co-packaged drugs, we have been 
responding to these applications on a case-by-case basis by applying 
the statutory standards for safety and effectiveness, as well as 
applicable regulations for new drugs.
    The Agency interprets the act of shrink-wrapping or otherwise 
packaging two products together, in the absence of any alternative 
explanation for the packaging such as ``convenience'' or ``value'' 
pack, to be an implied claim that the products are intended to be used 
together for a common or related therapeutic purpose. In the case of a 
dietary supplement co-packaged with a drug, the co-packaging implies 
that the dietary supplement is intended to be used for a therapeutic 
purpose, and the dietary supplement will be considered a drug under the 
FD&C Act (see footnote 1 for additional discussion of the treatment of 
dietary supplements as drugs when used in combination with a drug).
    In the absence of another explanation (such as the ``convenience 
kit'' discussed later in this section), packaging two products together 
makes an implied claim that they are safe and effective when used 
together. Without proper approval, these products are considered 
unapproved drugs under section 505(a) of the FD&C Act. Without approved 
labeling, such products would also be considered misbranded under 
section 502 of the FD&C Act, including under section 502(n).
    In some cases, however, OTC drugs are packaged together for 
convenience, such as a ``travel kit'' or ``convenience kit'' that 
includes an antiperspirant, an internal analgesic, toothpaste, 
sunscreen, and/or a sleep aid. In other cases, OTC drugs might be 
packaged together as two or more shrink-wrapped cartons to be sold as 
one unit identified as a ``special value'' or ``value pack.'' These 
individual drugs are not intended to be used together for a common or 
related therapeutic purpose. Therefore, these types of kits do not meet 
the proposed definition of co-packaged drug and would not be subject to 
the requirements of this proposed rule.
5. Drug
    We propose to define ``drug'' as having the same meaning given this 
term in section 201(g) of the FD&C Act and including biological 
products as defined in section 351 of the PHS Act that also meet the 
definition of ``drug'' in section 201(g) of the FD&C Act, but not 
including any product that meets the definition of ``device'' under the 
FD&C Act (21 U.S.C. 301, et seq.).
6. Fixed-Combination Drug
    We propose to define ``fixed-combination drug'' to mean a drug in 
which two or more active ingredients are combined at a fixed dosage in 
a single dosage form.
    We are not proposing to include individual natural-source drugs 
under the definition of ``fixed-combination drug,'' even when they may 
contain more than one active component. We do not believe that the 
current fixed-combination drug regulations were intended to or should 
apply to a drug that is derived from a single, naturally occurring raw 
material. Fixed-combination drugs involve deliberate combinations of 
distinct, single active ingredients, either produced synthetically or 
isolated and purified from a natural source.
    Examples of prescription fixed-combination drugs include the 
following: ARTHROTEC (diclofenac sodium and misoprostol tablets) for 
the treatment of osteoarthritis or rheumatoid arthritis in patients at 
high risk of developing nonsteroidal anti-inflammatory drug (NSAID)-
induced gastric or duodenal ulcers; COMBIVIR (lamivudine and zidovudine 
tablets) for the treatment of HIV infection; and LOTREL (amlodipine 
besylate and benazepril capsules) for the treatment of hypertension 
(one of a large number of antihypertensive fixed-combination drugs). 
Examples of fixed-combination OTC drug products marketed in accordance 
with OTC drug monographs include, a wide variety of ``cough/cold'' 
fixed-combination drugs (containing analgesics-antipyretics, cough 
suppressants, decongestants, and antihistamines). Fixed-combination OTC 
drug products marketed under an NDA include Imodium Multi-Symptom 
Relief (loperamide hydrochloride and simethicone tablets), to relieve 
diarrhea and gas, and Pepcid Complete (famotidine, calcium carbonate, 
and magnesium hydroxide chewable tablets), to relieve heartburn.
    There are also certain products that, although they are composed of 
or derived from a single animal, botanical, prokaryotic, fungal, or 
viral raw material, combine two or more separated and purified active 
ingredients and therefore would be regarded as fixed-combination drugs 
subject to the requirements of proposed Sec.  300.53. These include any 
products made by inducing and/or copurifying,

[[Page 79782]]

and then combining, two or more different macromolecules derived from 
the same raw material where each macromolecule in the fixed-combination 
drug is necessary to achieve the claimed effect(s).
    Our current and long-standing policy is to apply the requirements 
of current Sec.  300.50 to fixed-combination drugs that are created by 
combining two or more macromolecules that are separate active 
ingredients. It should be noted, however, that products such as whole 
blood, individual or pooled transfusible blood components (e.g., pooled 
platelets), pooled plasma products, and plasma derivatives from human 
or animal sources (e.g., immune globulins of general or particular 
specificity) would not be regarded as fixed-combination drugs, which 
also would be consistent with our current and long-standing policy.
    We also have a current and long-standing policy of applying the 
requirements of current Sec.  300.50 to products formed by inducing and 
then purifying two or more macromolecules (proteins or other 
macromolecules) derived from the same raw material where each induced 
and purified protein or other macromolecule is necessary to achieve the 
claimed effect(s) of the product. Inducing macromolecules usually 
involves treating a source material to elicit the production of two or 
more macromolecules from a single raw material source. For example, a 
single animal (raw material source) might be immunized with multiple 
antigens to induce antibodies of multiple specificities. Another 
example is combining two treatments that enhance production of 
different proteins in one cell line, with both sets of proteins 
contributing to the claimed effect of the product. Even for a product 
created using a process in which the raw material is not manipulated, 
if an applicant makes claims about different specific macromolecules 
contained in the product, it would be considered a fixed-combination 
drug and the applicant would be required to demonstrate the 
contribution of each active ingredient to the claimed effect.
    Similarly, a product derived from the purification of an entire set 
of macromolecules, such as immunoglobulin derived from human plasma, 
would not be regarded as a fixed-combination drug.
    Copurifying macromolecules involves selective purification and 
extraction of multiple macromolecules away from the rest of the raw 
material, such as that which occurs during the development of the 
fibrinogen component of a fibrin/thrombin sealant product. The 
fibrinogen component can be isolated from plasma in such a way that it 
contains both fibrinogen and Factor XIII. If the copurified fibrinogen 
and Factor XIII are isolated and measured to determine whether each 
improves the performance of the other, and it is determined that they 
both make a contribution to the fibrin sealant (e.g., hemostatic) 
activity of the product, such a product would be considered a fixed-
combination drug with three active ingredients: Thrombin, fibrinogen, 
and Factor XIII.
7. Fungal Raw Material
    We propose to define ``fungal raw material'' as a physically 
processed culture of a single-cell or multicellular organism, including 
yeasts, molds, and smut.
8. Interested Person
    We propose to define ``interested person'' to mean, with regard to 
a combination of two or more active ingredients under consideration for 
inclusion in an OTC monograph, any person who makes a submission under 
part 330 regarding safety or effectiveness.
9. Natural-Source Drug
    We propose to define ``natural-source drug'' as a drug composed of 
one single animal, botanical, prokaryotic, fungal, or viral raw 
material, or derived from one such material using a manufacturing 
process that involves only physical steps (e.g., solvent extraction, 
condensation, column purification), and does not involve a chemical 
reaction (other than esterification, viral inactivation, or prokaryote 
inactivation) that would modify the covalent bonds of any substance in 
the original material. This would be true even though the natural-
source drug may be considered to contain multiple components that may 
contribute meaningfully to the drug's pharmacological or therapeutic 
activity.
    The composition of a natural-source drug may be adjusted for 
assuring quality (e.g., for assuring consistency or purity), but may 
not be changed in a way that would affect the product's activity (e.g., 
by selectively increasing or decreasing the concentration of particular 
components). In this way, we mean to distinguish natural-source drugs 
from synthetic substances, including synthetic mixtures.
    Examples of natural-source drugs include the following:

     Menotropins derived from the urine of postmenopausal 
women for the induction of ovulation in anovulatory infertile 
patients.
     Extract from porcine thyroid glands for treating 
hypothyroidism.
     Extract from porcine pancreas glands for treating 
pancreatic enzyme deficiency.
     Heparin sodium derived from porcine intestinal mucosa 
for anticoagulant therapy in prophylaxis and treatment of venous 
thrombosis.
     Psyllium husk fiber for treatment of constipation.
     Bermuda grass pollen allergenic extract.
     Catechins in green tea extract for treatment of genital 
warts.
     Polyclonal immunoglobulin to provide protection against 
infectious diseases.
     Prothrombin complex concentrate products used for 
urgent reversal of acquired coagulation factor deficiency induced by 
vitamin K antagonist therapy.

    Natural-source drugs differ from the drugs for which current Sec.  
300.50 was established in that they do not involve an intentional 
``combining'' of active ingredients. There is no discussion of this 
type of drug in the regulatory history of Sec.  300.50 or Sec.  
330.10(a)(4)(iv), and historically we have not applied the fixed-
combination drug requirements to products that contain active 
ingredients derived from a single, naturally-occurring source. 
Therefore, we believe that it is appropriate to make clear in the 
regulations that individual natural-source drugs are not fixed-
combination drugs and are not subject to this proposed rule.
    In addition, we contemplate that the raw materials contained in 
natural-source drugs exist in nature or result from a traditional 
breeding practice or a conventional laboratory gene modification 
technique such as ultraviolet radiation or non-targeted chemical 
mutagenesis. Plants or animals that are genetically modified in these 
ways result from a process that can produce multiple, unpredictable 
variants of the genome of an organism, similar to the process that 
occurs in nature. In contrast, genetic modification by a process 
involving recombinant DNA technology or any other gene modification 
technology produces a deliberate change to the genome of an organism. 
Thus, plants, animals, or microorganisms whose genetic structure has 
been modified by recombinant DNA technology would not be appropriate 
sources for natural-source drugs because the intent is to produce a 
particular gene product with well-defined active ingredients. Included 
among such products are transgenic plants, transgenic animals, and 
recombinant DNA-derived microorganisms and other cells.
    Similarly, we assume that the components of natural-source drugs 
have not been altered or deliberately mixed in a way that would change 
the

[[Page 79783]]

activity or effect of the product. We understand that, for certain 
products, such as fish-oil mixtures or conjugated estrogens, it is 
important to adjust the levels of the individual components to maintain 
uniformity of effect and overall product quality. This kind of 
adjustment would not be expected to alter the effect or activity of the 
product and is an acceptable practice for maintaining quality. However, 
a product that is the result of a deliberate, selective extraction and 
mixing of components, even if derived from a naturally occurring raw 
material, does not meet the definition of natural-source drug, but 
rather would be considered a fixed-combination drug. These products are 
further described in the discussion of inducing and/or copurifying two 
or more different macromolecules under the definition of ``fixed-
combination drug'' in section III.A.6.
    In addition, drugs made from multiple raw materials (such as a 
product made from parts of different plants) would not be considered 
natural-source drugs because they involve an intentional combining of 
multiple different raw materials, each of which might contain a 
separate active ingredient, for the purpose of treating a particular 
disease, condition, or set of symptoms. One example of such a drug is 
botulinum antitoxin, which is made by immunizing several horses with 
one of seven distinct botulinum toxins and blending the plasma from the 
animals to make a single product that is active against seven toxins. 
Mixed (multiple source) allergenic products are another example of a 
drug made by intentionally combining more than one raw material. 
Stallergenes' ORALAIR, a sublingual allergen extract, contains a 
mixture of freeze-dried extracts from the pollens of five grasses, 
including Kentucky bluegrass, orchard, perennial rye, sweet vernal, and 
timothy. These types of products would be subject to this proposed 
rule, but may be eligible for a waiver under proposed Sec.  300.60 on 
the grounds that clinical trials to show that each component 
contributes to the effect of the combination would be scientifically 
infeasible.
    Finally, it is important to note that, although the requirements of 
proposed Sec.  300.53 would not be applied to natural-source drugs, to 
obtain marketing approval of these products, an applicant would still 
need to provide evidence demonstrating that the natural-source drug 
meets the requirements for approval under section 505 of the FD&C Act 
or section 351 of the PHS Act, or is appropriate for inclusion in an 
OTC monograph.
10. Prokaryotic Raw Material
    We propose to define ``prokaryotic raw material'' as a physically 
processed culture of bacteria or other cellular organism lacking a true 
nucleus and nuclear membrane. Prokaryotes are composed of bacteria and 
blue-green bacteria (formerly referred to as blue-green algae).
11. Rational Concurrent Therapy
    We propose to define ``rational concurrent therapy'' as medically 
appropriate treatment for a patient population defined in the drug's 
labeling. That is, the defined patient population can benefit from all 
of the active ingredients at the specific doses present, given for a 
similar duration of treatment, and not be adversely affected by 
receiving them in combination.
    When we refer to a ``defined patient population'' in this 
definition, we mean that there is an easily identifiable patient 
population for the combination in question that will be specifically 
described in the drug's labeling. When we say that the defined patient 
population will not be adversely affected, we mean, for example, not 
adversely affected by being exposed to drugs that interact harmfully, 
being restricted to particular doses of a drug when a wider range of 
doses is needed for proper administration, and having to take two or 
more active ingredients as extended treatment when one or more of these 
ingredients may be needed only for a short period of time. Rational 
concurrent therapy does allow for the treatment of more than one 
indication, as long as there is a defined patient population for which 
the combination provides medically appropriate treatment.
    The requirement that the patient population be identified in the 
label is currently required under Sec.  300.50, but is not currently in 
Sec.  330.10. However, identifying the patient population has been the 
practice in circumstances when an OTC drug is only appropriate for 
certain patient populations, so we do not believe this proposed 
requirement will require a change in existing labeling for OTC 
monograph drugs.
12. Single Animal Raw Material
    We propose to define ``single animal raw material'' as a single 
organ, human cell, tissue, cellular- and tissue-based product, or 
bodily fluid collected from any human or nonhuman animal species that 
has not been genetically modified using recombinant DNA technology or 
any other process that deliberately changes the genome. In certain 
cases, multiple parts of an animal may be used in a single animal raw 
material. For example, a drug that is derived from an invertebrate 
animal species (including multiple parts or all of an invertebrate 
animal) may be considered a single animal raw material. The organs and 
tissues of invertebrate species (e.g., insects) tend to be much smaller 
than those of most vertebrates. Consequently, with invertebrates, it is 
much more likely that a combination of more than one organ, tissue, or 
fluid--or an entire organism--will be used for various therapeutic 
indications.
13. Viral Raw Material
    We propose to define ``viral raw material'' as a minimally 
processed culture of a virus. The virus in culture may exist in nature 
or may have been attenuated or inactivated through selection or by 
physical and/or chemical means.
14. Waived Product
    We propose to define ``waived product'' to mean: (1) An approved 
fixed-combination or co-packaged product for which a waiver has been 
granted under Sec.  300.60 or (2) a combination of active ingredients 
included in an OTC monograph that has been GRASE for which a waiver has 
been granted under Sec.  300.60.

B. Applicability of the Proposed Rule (Proposed Sec.  300.51)

    Proposed Sec.  300.51 states that subpart B of part 300 (currently 
containing the provisions on prescription fixed-combination drugs for 
humans) applies to both prescription and OTC fixed-combination and co-
packaged drugs that are subject to approval under an NDA under section 
505 of the FD&C Act, or a BLA under section 351 of the PHS Act, and to 
combinations of active ingredients under consideration for inclusion in 
an OTC monograph in accordance with part 330. It does not apply to 
individual natural-source drugs.
    This proposed rule applies to prescription or OTC fixed-combination 
or co-packaged drugs that require an NDA or a BLA for marketing 
approval. In addition, OTC combinations cannot be GRASE under Sec.  
330.10 unless they meet the requirements in proposed Sec.  300.53. This 
means that, consistent with our current regulations, compliance with 
proposed Sec.  300.53 would be necessary to add a new combination of 
active ingredients to an OTC monograph in accordance with Sec.  
330.10(a)(12). Or, to obtain approval of a combination of two active 
ingredients that are each contained in a different final monograph, an 
applicant may

[[Page 79784]]

submit an NDA deviation under Sec.  330.11, which would also have to 
comply with proposed Sec.  300.53.
    The proposed rule would not apply to combination products \8\ 
involving devices (e.g., drug/medical device or biological product/
medical device combinations) and does not alter determination of 
primary jurisdiction for combination products under part 3 (21 CFR part 
3). Part 3, entitled ``Product Jurisdiction,'' governs the 
determination of what organizational component within FDA will be 
designated to have primary jurisdiction for premarket review and 
regulation of combination products (i.e., any combination of a drug and 
device; a device and a biological product; a biological product and a 
drug; or a drug, biological product, and a device). A fixed-combination 
or co-packaged drug may also meet the definition of a ``biological 
product'' and be assigned to either the Center for Drug Evaluation and 
Research or the Center for Biologics Evaluation and Research for FDA 
organizational jurisdiction purposes. This does not affect the 
applicability of this proposed rule.
---------------------------------------------------------------------------

    \8\ As stated in this section of the document, under Sec.  3.2 
(21 CFR 3.2), a ``combination product'' involves a combination, 
under specified circumstances, of two or more regulated components 
in one of the following combinations: Drug/device, biological 
product/device, drug/biological product, or drug/device/biological 
product (see Sec.  3.2(e)(1) through (4)).
---------------------------------------------------------------------------

C. Requirements of the Proposed Rule (Proposed Sec.  300.53)

    Proposed Sec.  300.53 sets forth the requirements for combinations 
of active ingredients under consideration for inclusion in an OTC 
monograph and prescription and OTC fixed-combination and co-packaged 
drugs. Under proposed Sec.  300.53, two or more active ingredients may 
be combined in a fixed-combination or co-packaged drug or included as a 
combination in an OTC monograph when the proposed requirements are met.
    First, under proposed Sec.  300.53(a)(1), each active ingredient 
must make a contribution to the effect(s) of the combination, enhance 
the safety or effectiveness of an active ingredient, or minimize the 
potential for abuse of an active ingredient. Most often, two or more 
active ingredients are combined in a single dosage form or are co-
packaged so that patients or consumers who are taking both active 
ingredients can more conveniently obtain the therapeutic benefits of 
each active ingredient. In this case, an applicant or interested person 
would be required to show that each active ingredient contributes to 
the effect(s) of the combination. In other cases, active ingredients 
are combined to enhance the safety or effectiveness of one or more of 
the active ingredients or to minimize the potential for abuse of one of 
the active ingredients. In these cases, an applicant or interested 
person would be required to demonstrate that the active ingredients 
perform as claimed.
    Second, under proposed Sec.  300.53(a)(2), the dosage of each 
active ingredient (amount, frequency of administration, and duration of 
use) must be such that the combination is safe and effective and 
provides rational concurrent therapy. We note that, in the context of 
the OTC monograph, some monographs indicate that dosing for 
combinations should not ``exceed any maximum dosage limits established 
for the individual ingredients in the applicable OTC drug monograph,'' 
but remain silent on minimum dosage limits. For a combination under a 
monograph or proposed to be included in a monograph, to satisfy the 
requirements of either this proposed rule or current Sec.  
330.10(a)(4)(iv), the dosing for the individual active ingredients in 
the combination must not exceed the maximum dosage limits for the 
single entities (if these are marketed separately) and must meet the 
minimum effective dosage established in the monograph. For example, if 
the monograph specifies that an individual active ingredient is to be 
dosed every 4 hours, that active ingredient could not be combined with 
another active ingredient that is to be dosed every 6 to 8 hours 
because there is no way to write directions for use with a dosing 
interval that would achieve the minimum effective dose for both 
ingredients without exceeding the maximum dose for one of them.
    We note that, under section 351(d)(1) of the PHS Act, a BLA must 
demonstrate that the product is ``safe, pure, and potent'' to be 
approvable; whereas, section 505(d) of the FD&C Act requires proof of 
safety and substantial evidence of effectiveness for approval of an 
NDA. Nevertheless, we believe that referring to effectiveness in 
proposed Sec.  300.53(a) is appropriate and consistent with statutory 
and regulatory provisions regarding biological products. This is 
because the Agency has long interpreted ``potency'' to include 
effectiveness.\9\
---------------------------------------------------------------------------

    \9\ 21 CFR 600.3(s); see also guidance for industry on 
``Providing Clinical Evidence of Effectiveness for Human Drug and 
Biological Products,'' available at http://www.fda.gov/Drugs under 
``Guidances (Drugs).''
---------------------------------------------------------------------------

    Under proposed Sec.  300.53(b)(1), we explain that applicants or 
interested persons must state the intended use of each active 
ingredient in the combination. This requirement ensures that the 
therapeutic purpose of all active ingredients, even those that might 
not be considered active ingredients in other contexts, is claimed. As 
noted in footnote 1 and under the definition of ``active ingredient'' 
in section III.A.l., FDA considers a dietary supplement to be a drug 
and considers it to be intended to furnish a therapeutic effect when it 
is combined with a drug in a prescription or OTC fixed-combination or 
co-packaged drug or is part of a combination under consideration for 
inclusion in an OTC monograph.
    Under proposed Sec.  300.53(b)(2), we explain that applicants and 
interested persons must provide sufficient evidence to demonstrate that 
their products meet the requirements of proposed Sec.  300.53(a), 
including evidence demonstrating the contribution of each active 
ingredient to the effect(s) of the combination. The amount and type of 
data and information needed to demonstrate such a contribution may vary 
depending on a range of factors, including the types and number of 
active ingredients, the nature of the therapeutic intent of the product 
(e.g., a combination of active ingredients intended to treat the same 
sign or symptom; a combination of active ingredients intended to treat 
different, but concurrently occurring, signs or symptoms; or a 
combination in which one ingredient is intended only to potentiate the 
other ingredient that is active against the disease or condition), and 
whether the individual active ingredients are already approved as 
single agents for the same indication(s) as are sought for the fixed-
combination or co-packaged drug.
    The most common scenario for development of fixed-combination or 
co-packaged drugs involves combining two or more drugs that are already 
approved for use as single agents. In these types of fixed-combination 
or co-packaged drugs, the drugs to be combined may be directed at the 
same sign or symptom of the same disease or condition, at different 
signs or symptoms of the same disease or condition, or at different 
diseases or conditions. Less often, a fixed-combination or co-packaged 
drug will include one approved drug and an additional active ingredient 
that is intended to enhance its safety or effectiveness but that has no 
independent therapeutic effect. For fixed-combination or co-packaged 
drugs that are made up of already-approved drugs, the individual drugs 
in the combination are generally well-characterized and development is

[[Page 79785]]

focused primarily on characterizing the safety and effectiveness of the 
combination and the contribution of each component. In these cases, the 
data needed to demonstrate the contribution of each active ingredient 
to the effect of the combination could include some or all of the 
following: Controlled clinical trials showing a contribution of each 
active ingredient to the claimed effect; controlled studies showing an 
effect of each active ingredient on a pharmacologic parameter or 
biomarker considered predictive of the therapeutic effect; clinical 
pharmacology data; in vitro data; and/or animal model data.
    FDA is also aware of a growing interest in the development of two 
or more new investigational drugs (i.e., drugs that have not been 
previously developed) for use in combination, either as individual 
agents labeled for use with one another or as a fixed-combination or 
co-packaged drug. There is particular interest in such development for 
targeted cancer and anti-infective therapies. In contrast to fixed-
combinations or co-packages of previously approved drugs, new 
investigational products are not well-characterized. Therefore, this 
type of development is inherently more complex and requires studies to 
characterize not only the combination, but also the individual agents 
to the extent necessary and feasible. Because of the complexity 
involved in development of two new investigational drugs, FDA has 
provided guidance to assist sponsors (see guidance for industry on 
``Codevelopment of Two or More New Investigational Drugs for Use in 
Combination,'' available at http://www.fda.gov/Drugs under ``Guidances 
(Drugs)'').
    Proposed Sec.  300.53(c) states that the statement and evidence 
specified in proposed Sec.  300.53(b) must be provided in an NDA or a 
BLA or, if an interested person seeks to include the combination in an 
OTC monograph, in a submission under part 330. The information showing 
that a fixed-combination or co-packaged drug meets the requirements of 
Sec.  300.53 would be included in the data on effectiveness that is 
needed for the approval of an NDA under Sec.  314.50(d)(5) (21 CFR 
314.50(d)(5)), for the approval of a BLA under Sec.  601.2(a) (21 CFR 
601.2(a)), or for inclusion of the combination in an OTC monograph 
under part 330. Regarding NDAs, this would include an NDA requesting 
approval of an OTC combination that deviates in some respect from a 
final monograph in accordance with Sec.  330.11. During the development 
of a fixed-combination or co-packaged drug, we may generally discuss 
with the sponsor what clinical trial data or other information might be 
needed to demonstrate that the product meets these requirements.
    In the following subsections of this document, we discuss the data 
and information that might be needed to demonstrate the contribution of 
each active ingredient to the effect of a combination. As this 
discussion illustrates, there is considerable flexibility in the amount 
and types of new or existing data that would be needed, and applicants 
and interested persons should provide scientific justification for the 
testing and data that might be needed to discuss the matter with FDA. 
We also understand that, in some cases, it may be medically 
unreasonable or unethical or scientifically infeasible to conduct new 
clinical studies, and existing data may not be adequate to fulfill the 
requirements of proposed Sec.  300.53. In these cases, a waiver from 
the requirement to demonstrate the contribution of each active 
ingredient to the claimed effect may be an option (see proposed Sec.  
300.60).
    Finally, it is important to note that it is not always a 
requirement that a fixed-combination formulation be used in a factorial 
study. The data from a factorial study in which the individual active 
ingredients are administered separately can be relied upon to support 
an application for a fixed-combination drug if the study data is linked 
to a fixed-combination formulation by a bioavailability study.
1. Combinations in Which the Individual Active Ingredients Are Directed 
at the Same Sign, Symptom, or Condition
    Active ingredients that have different mechanisms of action may be 
combined to treat the same sign, symptom, or condition if the active 
ingredients, when used together, can be proven to provide a benefit 
greater than each of the active ingredients used alone at its 
therapeutic dose. For such combinations, in which the effect of each 
active ingredient is directed at the same sign or symptom of a disease 
or condition, a factorial study is typically used to demonstrate that 
the combination has a larger treatment effect than one or more of the 
active ingredients alone. A factorial study for a combination of n 
active ingredients would ordinarily be designed to show that the n 
active ingredient combination is more effective than all possible n-1 
active ingredient combinations. Thus, for a combination with two active 
ingredients, a factorial study would have three arms--the combination 
(AB) and the individual drugs contained within it (A) and (B)--and 
would be designed to demonstrate that AB has a larger effect than A 
alone and B alone (AB versus A and AB versus B). For a combination with 
four active ingredients, a factorial design would compare the 
combination (ABCD) to all possible three-drug combinations of the four 
active ingredients (ABC, ABD, ACD, and BCD).
    If a factorial study is needed to demonstrate the contribution of 
each active ingredient in a combination, and the individual active 
ingredients are all previously approved and the magnitude and duration 
of effect of each active ingredient is well characterized, it may be 
possible to conduct a study of shorter duration than was required for 
initial approval. It also may be possible to study the effect of the 
combination on a subset of the endpoints used for approval of the 
active ingredients, or even a different endpoint such as a 
pharmacological endpoint, if the active ingredient is well understood.
    In certain cases, a new factorial study may not be needed. For 
example, FDA guidance for industry on the development of combinations 
of antiretrovirals for the treatment of HIV describes situations in 
which existing data can be used to demonstrate the contribution of the 
individual active ingredients, including clinical data on use of the 
individual ingredients in a combination, in clinical pharmacologic 
data, and in nonclinical data (Ref. 6). As discussed in that guidance, 
for a fixed combination of two previously approved drugs in this class, 
new clinical data would ordinarily be needed only to demonstrate that 
the bioavailability of the fixed-combination drug is comparable to that 
of the active ingredients administered individually. The same would be 
true for a co-packaged drug developed for the treatment of HIV.
    The guidance also points out that, in some cases, it may be 
possible to use data from a previously approved fixed-combination drug 
to partially support an application for a new fixed-combination drug if 
the previously approved product is similar to the new product. 
Similarly, FDA guidance on demonstrating efficacy of fibrin sealant 
products recommends that overall efficacy of a fixed-combination fibrin 
sealant drug be demonstrated in clinical trials, but provides that the 
contribution of each active ingredient may be demonstrated using 
nonclinical methods (Ref. 7).
    In some cases, it may not be possible to conduct a factorial study 
because the study would be unethical. For example, it would be 
unethical to conduct a

[[Page 79786]]

factorial study with a mortality or heart attack outcome comparing a 
fixed-combination drug with two active ingredients to its individual 
active ingredients if both active ingredients have established 
beneficial effects on mortality or major morbidity endpoints (e.g., an 
antiplatelet drug and a lipid-lowering drug that each reduce the risk 
of death, stroke, and heart attack). In that case, subjects randomized 
to the single-drug groups would be denied therapy that is known to 
decrease the incidence of major cardiovascular events and death. On the 
other hand, a short-term study of the platelet-inhibiting and lipid-
lowering effects of the combination would be ethical and might support 
outcome claims, depending on available data or concomitant use of the 
drugs. Similarly, it may not be possible to compare an antiviral fixed-
combination drug to the individual active ingredients if there is known 
rapid development of resistance to monotherapy. It also may not be 
needed if the studies of the single entities used together show 
improved long-term effectiveness.
    In the case of combinations for which a factorial design is not 
possible, different approaches could be used to satisfy the requirement 
to demonstrate the contribution of each active ingredient to the effect 
of the combination by identifying an existing population in which the 
added effect of one of the active ingredients could be established. For 
example, for a fixed-combination drug containing an older antiplatelet 
active ingredient and a newer lipid-lowering active ingredient, 
existing studies of the lipid-lowering active ingredient may have 
included substantial subsets of subjects who were all receiving the 
antiplatelet active ingredient and who were randomized to the lipid-
lowering active ingredient or placebo. These subsets could potentially 
be used to demonstrate the added contribution of the lipid-lowering 
active ingredient. Or, if there were a newer antiplatelet drug 
(approved after the lipid-lowering active ingredient), there may be 
studies in which its effect when added to the lipid-lowering active 
ingredient had been established. In theory, the data from these studies 
may be adequate to support a general conclusion that a lipid-lowering 
active ingredient and an antiplatelet active ingredient can be expected 
to have independent and additive effects when used in combination.
    There are also practical constraints on the use of a factorial 
design as the number of active ingredients in a combination increases. 
The greater number of active ingredients in a combination, the greater 
number of comparisons must be performed to demonstrate that each active 
ingredient contributes to the effect of the combination. At some point, 
a factorial study design becomes infeasible. The approximate overall 
power of a factorial study equals the power of the individual 
comparisons raised to the nth power (exponent) where n is the total 
number of comparisons. So, demonstrating the contribution of each 
active ingredient of a five-ingredient combination requires five pair-
wise comparisons--the full combination (ABCDE) compared to each of the 
possible combinations of the individual active ingredients (ABCD, ABCE, 
ABDE, ACDE, and BCDE). If each of the comparisons is powered at 90 
percent, there is a 90 percent probability that any given comparison 
will reject the null (no-difference) hypothesis assuming the 
alternative hypothesis is true (i.e., there is a difference), but only 
about a 60 percent probability that all five null hypotheses will be 
simultaneously rejected (i.e., a 40 percent chance that one of the five 
comparisons will be an erroneous result). In general, for combinations 
with multiple active ingredients, each individual comparison in a 
factorial study should be sufficiently powered so that the overall 
power is at least 80 percent. However, it may not be feasible to enroll 
the number of subjects needed to provide sufficient power. If the 
number of active ingredients in a combination renders a factorial 
design infeasible, it may be possible to use data from studies 
evaluating combinations that contain only some of the active 
ingredients. It also may be possible to use, other types of clinical 
and nonclinical data and mechanistic information may be available to 
demonstrate the contributions of the individual active ingredients to 
the effect of the combination.
    Active ingredients that have the same mechanism of action and are 
directed at the same sign or symptom of a disease or condition should 
not ordinarily be combined unless there is some advantage over the 
individual active ingredients in terms of enhanced effectiveness, 
safety, patient acceptance, or quality of formulation. Thus, simply 
using half-doses of two pharmacologically similar drugs would not 
overcome the disadvantages of putting them in a fixed-combination 
unless the lower doses of the drugs had some advantages, such as fewer 
or different adverse events or greater effectiveness.
2. Combinations in Which One Active Ingredient Is Intended To Provide a 
Direct Effect That Enhances the Safety or Effectiveness of Another 
Active Ingredient
    For combinations in which one active ingredient is intended to: (1) 
Provide a direct effect that either potentiates or makes another active 
ingredient more tolerable (e.g., using carbidopa to provide a lower 
dose of levodopa to minimize side effects), (2) minimize an adverse 
reaction associated with another active ingredient (e.g., using 
pyridoxine to minimize the toxicity of isoniazid), or (3) reduce the 
abuse potential associated with another active ingredient (e.g., using 
an opioid antagonist to reduce the abuse potential of an oral opioid 
product following manipulation for purposes of abuse), a clinical trial 
comparing the combination to the disease-active ingredient alone would 
usually be necessary to demonstrate the contribution of each active 
ingredient. The trial would have to establish enhanced safety or 
effectiveness of the combination versus the disease-active ingredient 
alone. This would be true whether or not the disease-active ingredient 
has already been proven to be effective.
3. Combinations in Which Active Ingredients Are Directed at Different 
Signs or Symptoms of a Disease or Condition
    A factorial study is unlikely to be needed to demonstrate the 
contribution of each active ingredient in a combination where the 
active ingredients are directed at different signs or symptoms of a 
disease or condition. Instead, evidence that demonstrates that the 
active ingredients are effective individually and do not interfere with 
one another (e.g., pharmacokinetic data) is likely to be adequate to 
demonstrate the contribution of each active ingredient in this case. 
However, if there is a real possibility that an active ingredient could 
affect the safety or effectiveness of another active ingredient (e.g., 
an active ingredient intended to treat cough might interfere with the 
effect of a nasal decongestant), a factorial study or other data would 
probably be needed to demonstrate that the safety or effectiveness of 
any of the active ingredients is not diminished by combining them.
    Many OTC drug monographs, such as the cold cough, allergy, 
bronchodilator, and anti-asthmatic drug products monograph (part 341), 
describe acceptable combinations of active ingredients directed at 
different

[[Page 79787]]

symptoms arising from a single condition, such as a cold. One example 
of this would be a fixed-combination drug containing an antipyretic, an 
antitussive, and a nasal decongestant directed at fever, cough, and 
congestion, respectively. Combinations such as this, directed at 
different signs or symptoms of the same disease or condition, would 
generally not need a factorial study because each active ingredient 
would be expected to have its usual, independent effect on a particular 
symptom, and would not be expected to affect the other symptoms.
4. Combinations in Which the Active Ingredients Are Directed at 
Different Diseases or Conditions
    For combinations in which the active ingredients are directed at 
different diseases or conditions (e.g., common comorbid diseases), it 
would also generally be expected that each active ingredient would have 
its usual and independent effect on the disease or condition. Thus, for 
these types of combinations, it would usually be possible to rely on 
data demonstrating that the active ingredients are safe and effective 
when used independently and that no active ingredient interferes with 
the effect of another. This requirement can usually be satisfied by 
pharmacokinetic data.

D. Combining One or More Active Ingredients With a Natural-Source Drug, 
a Waived Product, or a Combination Already Described in an OTC 
Monograph (Proposed Sec.  300.55)

    Proposed Sec.  300.55(a) states that, when a natural-source drug is 
combined with any other type of active ingredient, the natural-source 
drug will be considered a single active ingredient for the purposes of 
fulfilling the requirements of Sec.  300.53. This section is intended 
to make clear that, for a combination of a natural-source drug and any 
other active ingredient, proposed Sec.  300.53 would not be interpreted 
to apply to the components of the natural-source drug.
    Proposed Sec.  300.55(b) states that, when a natural-source drug is 
combined with one or more additional natural-source drugs, each 
natural-source drug in the combination will be considered a single 
active ingredient for the purposes of fulfilling the requirements of 
Sec.  300.53. This is intended to clarify that, when a natural-source 
drug is combined with another such product, proposed Sec.  300.53 would 
not be interpreted to apply to the components in the natural-source 
drugs.
    Proposed Sec.  300.55(c) states that, when a waived product is 
combined with any other type of active ingredient, the waived product 
will be considered a single active ingredient for the purposes of 
fulfilling the requirements of Sec.  300.53. This is intended to 
clarify that, when a waived product is combined with any other active 
ingredient, proposed Sec.  300.53 would not be interpreted to apply to 
the components of the waived product. Waived products are discussed in 
section III.E.
    It is likely that many of these types of combinations would be 
eligible for a waiver under Sec.  300.60, as discussed in section 
III.E.

E. Waiver (Proposed Sec.  300.60)

    Proposed Sec.  300.60(a) states that ``FDA may, at the request of 
an applicant or interested person or on its own initiative, grant a 
waiver of any of the requirements under Sec.  300.53 with regard to a 
fixed-combination or co-packaged drug that is the subject of a pending 
application under section 505 of the FD&C Act or section 351 of the PHS 
Act, or a combination of active ingredients under consideration for 
inclusion in an OTC monograph in accordance with part 330, if it finds 
one of the following: (1) There is a reasonable rationale for the 
combination of the individual active ingredients, and compliance with 
any of the requirements of Sec.  300.53 would be infeasible or 
medically unreasonable or unethical; or (2) the product contains all or 
a subset of the known or probable components in the same ratio as a 
natural-source drug or a waived product, provided the product is 
intended for the same conditions of use as the natural-source drug or 
the waived product; there is a reasonable basis to conclude that the 
product would provide a comparable clinical effect to the natural-
source drug or the waived product; and, for products containing large 
molecules (macromolecules), the ingredients have the same principal 
molecular structural features and overall mechanism of action.''
    Applicants or interested persons may be granted a waiver from some 
or all of the requirements of proposed Sec.  300.53, depending on the 
evidence submitted.
1. Reasonable Rationale
    Proposed Sec.  300.60(a) requires that there be a reasonable 
rationale for the combination of the individual active ingredients in 
the proposed combination. This requirement ensures that all of the 
active ingredients in combinations that receive a waiver are 
appropriate and not extraneously added to the combination in the hope 
of receiving a waiver. Applicants might fulfill this requirement by 
referring to existing knowledge or providing data from in vitro or in 
vivo studies in animals or humans.
2. Infeasibility
    Compliance with the requirements of Sec.  300.53 might be 
infeasible if a proposed combination has so many active ingredients 
that a factorial study would become absurd (see discussion of 
statistical issues with large factorial studies in section III.C), and 
there is no other alternative method to demonstrate the contribution of 
each active ingredient to the effect of the combination.
    Among the types of products for which we would expect to grant a 
waiver are products used in traditional medicine that are composed of 
or derived from multiple raw materials from a single source or from raw 
materials from multiple sources. These products include the following:

     Traditional botanical products composed of multiple 
botanical raw materials in fixed ratios. These botanical products 
may be composed of or derived from multiple parts of the same 
species of plant or from parts of different plant species; \10\
---------------------------------------------------------------------------

    \10\ An example of a traditional medicinal product made by 
combining several parts of a single species of plant is Chinese 
lobelia herb (whole plant with roots, rhizomes, stems, leaves, and 
flowers of Lobelia chinensis Lour.), used to treat anasarca and 
ascites. Some traditional medicines combine multiple plants with 
different properties. For example, Wuling San, which contains Cortex 
cinnamomi, Rhizoma atractylodis macrocephalae, Rhizoma alismatis, 
Poria, and Polyporus umbellatus, has been used to treat oliguria 
caused by nephritis or renal failure. And, Sishen Wan, which 
contains Fructus psoraleae, Fructus schisandrae, Semen myristicae, 
and Fructus evodiae, is used in traditional Chinese medicine to 
treat colitis.
---------------------------------------------------------------------------

     traditional medicinal products composed of multiple 
parts of animals; and
     traditional medicinal products composed of substances 
derived from more than one type of natural source (e.g., a botanical 
raw material and a single animal raw material). These products are 
sometimes used in combination with certain minerals.
     Cellular and gene therapies.

    In most cases, these products have so many active ingredients that 
studies to demonstrate the contribution of each to the effect of the 
combination would be infeasible. For example, to show the clinical 
contribution of each active ingredient of a five-active ingredient 
mixture of raw materials, the study might require a minimum of six or 
seven arms: One arm for the five-active ingredient product, an arm for 
each of the five different four-active ingredient treatments (each 
omitting one component), and possibly a placebo (see section III.C for 
a full discussion of clinical trial design to fulfill the requirements 
of this proposed rule).

[[Page 79788]]

Such a study would be difficult, if not impossible, to conduct.
    Therefore, we generally expect to grant a waiver for these 
traditional products that have a long history of use as a single 
medicinal product (i.e., in a single solution, tablet, paste, or other 
form), and that are prepared according to a standardized, published 
methodology (e.g., pulverization, decoction, expression, aqueous 
extraction, ethanolic extraction) such as those described in an 
official pharmacopeia or compendium or a related publication.
    We also expect that we would waive the requirements of this 
proposed rule for certain allergenic products. Allergen patch tests are 
diagnostic tests applied to the surface of the skin to determine the 
specific causes of contact dermatitis. An allergenic patch test kit may 
contain individual patches in which several chemicals that may elicit 
allergic contact dermatitis are mixed (e.g., black rubber mix, paraben 
mix, fragrance mix). These tests are combined in this manner because a 
positive diagnosis regarding any of the allergens in the mix would 
result in the same clinical recommendation. Accordingly, there is a 
reasonable rationale for the product (i.e., the combination of its 
individual components), and it would be infeasible to require clinical 
trials to show that each component contributes to the effect of the 
combination.
    A single synthetic process that can produce a large mixture of 
random polymers (glatiramer acetate) may also be infeasible to study. 
These large mixtures of random polymers are analogous to the products 
discussed previously in that determining the contribution of each 
active ingredient would be similarly difficult.
3. Medically Unreasonable or Unethical
    Compliance with the requirements of proposed Sec.  300.53 might be 
considered medically unreasonable if, for example, each of the active 
ingredients of a planned fixed-combination drug where the combination 
is intended to affect survival is known to have an independent effect 
on survival (e.g., an antihypertensive and a lipid-lowering drug). In 
such a case, a factorial study with a survival endpoint (A versus B 
versus AB) should not be required because the single agent treatment 
arms would prevent patients from receiving the other known lifesaving 
therapy. If there are no alternative types of data that could be used 
to demonstrate the contribution of each active ingredient to the effect 
of the combination, this type of product could be eligible for a waiver 
(see related discussion of possible alternative data in section III.C).
    Similarly, a combination of active ingredients could be effective 
for a fatal disease for which there is no available therapy \11\ (e.g., 
a malignancy). Although it may be desirable to require an applicant to 
demonstrate the contribution of each active ingredient in the 
combination to the effect of the combination using a factorial study or 
other design with a single agent treatment arm, such a requirement may 
be medically unethical. If the combination is known to be effective and 
there is no available therapy, it would be unethical to withhold the 
combination from patients in one arm of the study. If there are no 
alternative types of data that could be used to demonstrate the 
contribution of each active ingredient to the effect of the 
combination, this type of product could be eligible for a waiver (see 
related discussion of possible alternative data in section III.C).
---------------------------------------------------------------------------

    \11\ For more discussion on FDA's consideration of ``available 
therapy,'' please see section III.B of the Guidance for Industry 
entitled ``Expedited Programs for Serious Conditions--Drugs and 
Biologics'', May 2014.
---------------------------------------------------------------------------

4. Subsets
    We do not believe it necessary, from the standpoint of safety or 
effectiveness, to impose the requirements of this proposed rule on 
combinations that have similar active ingredients to approved products 
for which the fixed-combination drug requirements have not been applied 
or have been waived. To receive a waiver as a subset under this 
proposed subsection, an applicant or interested person must demonstrate 
that the active ingredients contained in the product produce a 
comparable clinical effect to those contained in the original product. 
Merely encompassing a subset of the active ingredients contained in an 
approved product is not sufficient to gain a waiver under this 
provision. The subset of active ingredients must be sufficiently 
chemically similar to those contained in the approved product to 
achieve a comparable clinical effect. The concept of a subset 
contemplates that the active ingredients will remain in the same ratio, 
but will be a smaller amount. In other words, no product containing a 
greater percentage of a particular active ingredient than is present in 
the approved product would be eligible for a waiver.
    We propose to apply this concept to fixed-combination and co-
packaged drugs containing proteins or other large molecules 
(macromolecules). However, unlike for small molecules, proteins and 
macromolecules can differ in ways that do not change their clinical 
effect. Therefore, we believe it is more appropriate to require that, 
for fixed-combination and co-packaged drugs involving a subset of 
proteins or macromolecules, the active ingredients have the same 
principal molecular structural features and the same overall mechanism 
of action as the approved product. This requirement helps ensure that 
any structural difference would be minor and that the likelihood would 
be very low that any minor structural difference in an active 
ingredient would affect its contribution to the product's claimed 
effect.
    For example, an applicant might seek a waiver for a protein drug 
product with an active ingredient that differs in a post-translational 
modification from the active ingredient of the approved product. If 
there was sufficient evidence that the structural difference would be 
unlikely to alter the contribution of that active ingredient, a waiver 
might be appropriate. However, if it were known that the structural 
difference resulted in reduced effectiveness in related products, this 
might suggest a difference in the mechanism of action of the active 
ingredient in the proposed product, which would render the product 
ineligible for a waiver.
    Proposed Sec.  300.60(b) states that, if an applicant wishes to 
request a waiver, it must submit that request with supporting 
documentation in an application under section 505 of the FD&C Act or 
section 351 of the PHS Act. If an interested person wishes to request a 
waiver, that person must do so as part of a submission under part 330. 
The request for a waiver should explain why the applicant or interested 
person believes its product fulfills one or more of the waiver 
requirements of proposed Sec.  300.60(a). Submissions should include 
evidence demonstrating the safety and effectiveness of the product 
(including, where appropriate, dose-response studies) and, if 
appropriate, assurance that the active ingredients or active moieties 
in the proposed product have a comparable clinical effect as those in 
the approved product. For infeasibility waivers, applicants and 
interested persons should explain why they believe it would be 
infeasible to comply with the requirements of proposed Sec.  300.53. 
For example, they should explain why it is impossible to conduct any of 
the studies that would satisfy the requirements of the proposed rule, 
or, if conducting a study would be medically unreasonable or unethical, 
they should discuss why they believe that is the case.

[[Page 79789]]

    Proposed Sec.  300.60(c) states that ``FDA will provide appropriate 
written notice when the Agency grants a waiver on its own initiative, 
or grants or denies a request for a waiver. Fixed-combination and co-
packaged drugs and combinations of active ingredients under 
consideration for inclusion in an OTC monograph for which a waiver is 
granted must still meet all other applicable requirements under section 
505 of the FD&C Act, section 351 of the PHS Act, or Sec.  330.10(a)(4) 
of this chapter, as appropriate.'' The decision to grant a waiver under 
proposed Sec.  300.60(a) of the regulations is solely at the discretion 
of FDA. FDA may choose to grant a full or partial waiver. For products 
subject to an NDA or a BLA, we will notify the applicant in writing 
when we grant a waiver, or grant or deny a request for a waiver. For 
combinations seeking inclusion in an OTC monograph, because the citizen 
petition process described in 21 CFR 10.25 governs the addition of 
combinations to a monograph, we will place our decision to grant a 
waiver, or grant or deny a request for a waiver, in the docket related 
to the citizen petition. Products for which a waiver is granted must 
still be shown to meet the requirements for approval under section 505 
of the FD&C Act or section 351 of the PHS Act, as appropriate, 
including requirements for safety and effectiveness, or the 
requirements for classification of OTC drugs as GRASE under a 
monograph.

F. Revision of OTC Combination Provision (Proposed Sec.  
330.10(a)(4)(iv))

    As described in section III.B, proposed Sec.  300.51 states that 
the requirements of Sec.  300.53 would apply to prescription drugs as 
well as nonprescription drugs that are subject to approval under an 
NDA. Proposed Sec.  300.51 further states a combination of active 
ingredients cannot be GRASE under Sec.  330.10(a)(4)(iv) unless it 
meets the requirements in Sec.  300.53 (unless it is being marketed in 
accordance with an existing monograph that includes that particular 
combination).
    Under the proposed rule, Sec.  330.10(a)(4)(iv) would no longer 
contain separate provisions for OTC fixed-combination or co-packaged 
drugs. Instead, to make it easier to understand the regulations that 
apply to OTC combinations, we are proposing to revise Sec.  
330.10(a)(4)(iv) to state that a combination of two or more active 
ingredients that are individually determined to be safe and effective 
in accordance with the preceding requirements of part 330 must meet the 
requirements of subpart B of part 300 of the regulations to be GRASE 
and included in an OTC monograph. If such combination is granted a 
waiver under Sec.  300.60 of the regulations, it must still meet all 
other applicable requirements of this subsection to be GRASE and 
included in an OTC monograph. Unless otherwise specified in the 
applicable OTC monograph(s), combinations of active ingredients that 
are included in an OTC monograph may be used in either fixed-
combination or co-packaged drugs.

G. Changes to Regulations on Permissible Combinations of Biological 
Products (Proposed Sec.  610.17)

    Section 610.17 of the biological product regulations contains 
provisions on permissible combinations of biological products. Section 
610.17 states that a separate license is required when a licensed 
product is combined with another licensed product or with a 
nonlicensable therapeutic, prophylactic, or diagnostic substance.
    Under the proposed rule, biological products would be subject to 
the regulations in subpart B of part 300. To help make this clear to 
companies that have drug products subject to approval under section 351 
of the PHS Act regulations, we propose to revise Sec.  610.17 to state 
that a drug product subject to approval under section 351 of the PHS 
Act may not be combined with another drug except in accordance with 
subpart B of part 300.

IV. Legal Authority

    This rule, if finalized, would amend subpart B of part 300 in a 
manner consistent with the Agency's current understanding and 
application of that provision. FDA's legal authority to modify subpart 
B of part 300 arises from the same authority under which FDA initially 
issued the regulation (21 U.S.C. 331, 351, 352, 355, 361, 371) and 
section 330.1 (21 U.S.C. 321, 351, 352, 353, 355, 371) and also, with 
respect to biological products, section 351 of the PHS Act. Biological 
products are subject both to section 351 of the PHS Act and to the 
provisions of the FD&C Act and implementing regulations applicable to 
drugs, except that manufacturers of biological products covered by 
approved BLAs are not required to submit NDAs under section 505 of the 
FD&C Act. References to ``drugs'' in this section include biological 
products that are also drugs.
    Fixed-combination or co-packaged drugs generally purport to provide 
greater effectiveness (either in cumulative effect, by treating more 
than one indication, or by facilitating compliance) than either 
ingredient alone, or to enhance the safety or effectiveness of one of 
the active ingredients. Under the FD&C Act and related regulations, FDA 
has the authority to require specific types of evidence demonstrating 
that fixed-combination or co-packaged drugs and OTC monograph 
ingredients used in combination provide enhanced safety or 
effectiveness and can be labeled as such. This is because the use of 
any added active ingredient involves some risk, and that risk can only 
be justified by an added benefit in either safety or effectiveness. 
This proposed rule describes the requirements applicants must meet to 
demonstrate that their fixed-combination or co-packaged drugs are safe 
and effective.
    Section 701(a) of the FD&C Act (21 U.S.C. 371(a)) authorizes FDA to 
issue regulations for the efficient enforcement of the FD&C Act. FDA's 
rulemaking authority under section 701(a) has been broadly interpreted.
    Under section 502(a) of the FD&C Act, prescription and OTC drugs 
are deemed ``misbranded'' if their labeling is false or misleading ``in 
any particular.'' Section 201(n) of the FD&C Act states that labeling 
is misleading if it fails to reveal facts that are material with 
respect to the consequences that may result not only from the use of 
the product as labeled but from the use of the product under such 
conditions of use as are customary or usual. With regard to OTC drugs 
under a monograph, Sec.  330.1 explains that OTC drugs are GRASE and 
not misbranded if they meet ``each of the conditions contained in this 
part and each of the conditions contained in any applicable 
monograph.'' The standards for safety, effectiveness, and labeling are 
explained in Sec.  330.10(a)(4). Proof of safety may consist of 
``adequate tests by methods reasonably applicable to show the drug is 
safe under the prescribed, recommended, or suggested conditions of 
use.'' Proof of effectiveness must consist of ``controlled clinical 
investigations'' demonstrating that the drug ``will provide clinically 
significant relief of the type claimed.'' Information on how each 
ingredient in a combination contributes to the effect of the 
combination is a fact ``material'' to the consequences that may result 
from customary use of that product. Thus, it is within FDA's authority 
to require such testing as is necessary to establish the safety and 
effectiveness of ingredients used in combinations.
    With regard to prescription drugs or nonprescription drugs 
requiring approval under an NDA, section 505(c) and (d) of the FD&C Act 
directs FDA to refuse approval if there is a lack of substantial 
evidence that the drug will

[[Page 79790]]

have the effect that it purports or is represented to have under the 
conditions of use prescribed, recommended, or suggested in the proposed 
labeling thereof. The term ``substantial evidence'' is defined in 
section 505(d) of the FD&C Act as evidence consisting of adequate and 
well-controlled investigations, including clinical investigations, by 
experts qualified by scientific training and experience to evaluate the 
effectiveness of the drug involved, on the basis of which it could 
fairly and reasonably be concluded by such experts that the drug will 
have the effect it purports or is represented to have under the 
conditions of use prescribed, recommended, or suggested in the labeling 
or proposed labeling thereof. A drug product is not approvable if there 
is not ``substantial evidence'' effectiveness or sufficient evidence of 
safety. Thus, for fixed-combination and co-packaged drugs, FDA may 
require such testing as is necessary to establish that the drug is safe 
and effective for use under the conditions described in the labeling.
    Under Sec. Sec.  314.90 and 314.126(c), FDA has the authority to 
grant a waiver of any of the requirements for submitting an NDA or any 
criteria of an adequate and well-controlled study if it finds the 
applicant's compliance with a requirement is unnecessary or cannot be 
achieved, the applicant makes an alternative submission that satisfies 
the requirement, or the applicant otherwise justifies a waiver. 
Similarly, FDA may waive some or all of the requirements of this 
proposed rule if an applicant meets certain criteria. Waiver provisions 
are intended to give applicants flexibility to seek alternative ways of 
complying with the statutory standards for drug approval. Any drugs 
that receive a waiver under these provisions are still required to 
demonstrate safety and effectiveness to meet the statutory requirements 
for approval.
    Section 351 of the PHS Act provides legal authority for the Agency 
to regulate the labeling and shipment of biological products. Licenses 
for biological products are to be issued only upon a showing that the 
products meet standards ``designed to insure the continued safety, 
purity, and potency of such products'' prescribed in regulations 
(section 351(d) of the PHS Act). The ``potency'' of a biological 
product includes its effectiveness (21 CFR 600.3(s)). Section 351(b) of 
the PHS Act prohibits false labeling of a biological product. FDA's 
regulations in part 201 apply to all prescription drug products, 
including biological products.

V. Analysis of Impacts

A. Introduction

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all 
costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity). The Agency believes that this proposed rule is not a 
significant regulatory action as defined by Executive Order 12866.
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because the proposed requirements will have minimal 
economic impact on small entities (the unit cost of a request for a 
waiver as a percentage of the average of value of sales for a typical 
firm would be small--less than 0.15 percent of average sales for firms 
with 10 to 49 workers and even smaller for other small-size firms), the 
Agency anticipates that the proposed rule will not have a significant 
economic impact on a substantial number of small entities and seeks 
comments on its Initial Regulatory Flexibility Analysis.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that Agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $144 million, using the most current (2014) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
proposed rule to result in any 1-year expenditure that would meet or 
exceed this amount.

B. Summary of Benefits and Costs of the Proposed Rule

    The proposed rule would harmonize the requirements for prescription 
and OTC fixed-combination and co-packaged drugs and clarify the types 
of studies needed for approval of these products. Although we are 
unable to quantify or monetize all of the benefits, harmonizing and 
clarifying current policy would result in benefits to industry because 
there would be less uncertainty surrounding the requirements for 
approval of the affected products. This may in turn incentivize the 
development of new products. We estimated benefits associated with 
reduction in preparation and review time of information that would not 
be necessary if the proposed rule were in effect. Estimated annual 
benefits range between $651,891 and $977,836.
    Because the proposed requirements would codify current policy 
regarding the review of the affected products, there are no costs 
associated with these proposed requirements. However, the proposed rule 
would also create a provision under which sponsors can apply for a 
waiver when certain conditions are met. This proposed provision is a 
new requirement and would result in costs. Estimated annual costs of 
preparation and review of the proposed waiver range between $101,858 
and $152,787.
    The estimated annual benefits and costs are summarized in table 1.
    The full discussion of economic impacts is available (Ref. 8) in 
docket FDA-2011-N-0830 and at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

[[Page 79791]]

                                    Table 1--Summary of Benefits, Costs, and Distributional Effects of Proposed Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                       Discount rate
            Category               Primary estimate    Low estimate    High estimate   Year dollars      (percent)    Period covered         Notes
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                        Benefits
--------------------------------------------------------------------------------------------------------------------------------------------------------
Annualized Monetized (millions $/ $0.815............          $0.652          $0.978            2012               7         2014-33
 year).
                                  $0.815............           0.652           0.978            2012               3         2014-33
Annualized Quantified...........  ..................  ..............  ..............  ..............               7         2014-33
                                  ..................  ..............  ..............  ..............               3         2014-33
                                 -----------------------------------------------------------------------------------------------------------------------
Qualitative.....................   Additional benefits may arise for sponsors who may incur development costs that could be prevented by clarifying the
                                                                 requirements of the products covered by the proposed rule.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                          Costs
--------------------------------------------------------------------------------------------------------------------------------------------------------
Annualized Monetized (millions $/ 0.127.............           0.102           0.153            2012               7         2014-33
 year).
                                  $0.127............           0.102           0.153            2012               3         2014-33  Based on 10-15
                                                                                                                                       waivers per year.
                                 -----------------------------------------------------------------------------------------------------------------------
Annualized Quantified...........                                                      None estimated.
                                 -----------------------------------------------------------------------------------------------------------------------
Qualitative.....................                                                      None estimated.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                        Transfers
--------------------------------------------------------------------------------------------------------------------------------------------------------
Federal Annualized Monetized                                                          None estimated.
 (millions $/year).
                                 -----------------------------------------------------------------------------------------------------------------------
Other Annualized Monetized                                                            None estimated.
 (millions $/year).
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                         Effects
--------------------------------------------------------------------------------------------------------------------------------------------------------
State, Local, or Tribal Gov't...                                                           None.
Small Business..................   Based on the analysis, small business entities covered by the proposed rule could incur costs of $6,701 per waiver or
                                     up to 0.15 percent of average annual sales for entities with 10-49 employees and even smaller for all other firms.
Wages...........................                                                   No estimated effect.
Growth..........................                                                   No estimated effect.
--------------------------------------------------------------------------------------------------------------------------------------------------------

VI. Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions that 
are subject to review by OMB under the Paperwork Reduction Act of 1995 
(44 U.S.C. 3501-3520) (PRA). The title, description, and respondent 
description of the information collection are given under this section 
with an estimate of the annual reporting burden. Included in the 
estimate is the time for reviewing instructions, searching existing 
data sources, gathering and maintaining the data needed, and completing 
and reviewing the collection of information.
    We invite comments on these topics: (1) Whether the proposed 
collection of information is necessary for the proper performance of 
FDA's functions, including whether the information will have practical 
utility; (2) the accuracy of FDA's estimate of the burden of the 
proposed collection of information, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information to be collected; and (4) ways 
to minimize the burden of the collection of information on respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.
    Title: Regulations on Fixed-Combination and Co-Packaged Drugs and 
Combinations of Active Ingredients Under Consideration for Inclusion in 
An Over-the-Counter (OTC) Monograph.
    Description: The proposed rule would revise existing regulations in 
subpart B of part 300 on fixed-combination drugs and establish new 
provisions applicable to fixed-combination and co-packaged drugs and 
combinations of OTC active ingredients under consideration for 
inclusion in an OTC monograph. Although current Sec.  300.50 regulates 
prescription fixed-combination drugs and current Sec.  330.10(a)(4)(iv) 
regulates combinations of active ingredients under consideration for 
inclusion in an OTC monograph, they use slightly different language to 
achieve the same effect. In addition, current Sec.  300.50 does not 
mention co-packaged drugs even though the Agency's long-standing policy 
has been to apply the

[[Page 79792]]

requirements to co-packaged drugs. The proposed revisions would specify 
the kinds of studies that are needed to meet the requirements of this 
proposed rule, and would harmonize the requirements for prescription 
and OTC products and make them consistent with long-standing Agency 
policy.
    Under proposed Sec.  300.53(a), combinations of active ingredients 
under consideration for inclusion in an OTC monograph and fixed-
combination and co-packaged drugs must meet the following requirements: 
(1) Each active ingredient makes a contribution to the effect(s) of the 
combination, enhances the safety or effectiveness of an active 
ingredient, or minimizes the potential for abuse of an active 
ingredient and (2) the dosage of each active ingredient (amount, 
frequency of administration, and duration of use) is such that the 
combination is safe and effective and provides rational concurrent 
therapy.
    Under proposed Sec.  300.53(b), applicants and interested persons 
must: (1) State the intended use of each active ingredient in the 
combination and (2) submit sufficient evidence to meet the requirements 
in Sec.  300.53(a), including evidence demonstrating the contribution 
of each active ingredient to the effect(s) of the combination. The 
amount and types of data and information needed may vary and may 
include some or all of the following: Data from adequate and well-
controlled clinical trials, clinical pharmacology data, in vitro and 
animal model data, a basis for concluding there is a plausible 
pharmacologic rationale for the combination, and other relevant 
information.
    Under proposed Sec.  300.53(c), the statement and evidence 
specified in Sec.  300.53(b) must be included in an NDA (Sec.  314.50), 
a BLA (Sec.  601.2), or a submission under part 330 (Sec.  330.10) to 
support inclusion of a combination in an OTC monograph.
    FDA already has OMB approval for the submission of data or 
information under Sec. Sec.  314.50 and 601.2 (OMB control numbers 
0910-0001 and 0910-0338). The proposed regulations clarify current 
requirements and FDA policy and, therefore, the proposed changes would 
not result in the submission of additional data or information.
    In addition, the submission of data or information relating to 
Sec.  330.10(a)(4)(iv) for OTC monographs that have not yet been 
finalized would be submissions in response to a proposed rule, in the 
form of comments, which are excluded from the definition of 
``information'' under 5 CFR 1320.3(h)(4) of OMB regulations on the PRA 
(i.e., ``facts or opinions submitted in response to general 
solicitations of comments from the public, published in the Federal 
Register or other publications, regardless of the form or format 
thereof, provided that no person is required to supply specific 
information pertaining to the commenter, other than that necessary for 
self-identification, as a condition of the Agency's full consideration 
of the comment'').
    Under proposed Sec.  300.60(a), FDA may, at the request of an 
applicant or interested person or on its own initiative, grant a waiver 
of any of the requirements under proposed Sec.  300.53 with regard to a 
fixed-combination or co-packaged drug that is the subject of a pending 
NDA or BLA, or a combination of active ingredients under consideration 
for inclusion in an OTC monograph in accordance with part 330. To grant 
a waiver, one of the following must exist: (1) There is a reasonable 
rationale for the combination of the individual active ingredients in 
the product, and compliance with any of the requirements of Sec.  
300.53 would be infeasible or medically unreasonable or unethical; or 
(2) the product contains all or a subset of the known or probable 
components in the same ratio as a natural-source drug or a waived 
product, provided the product is intended for the same conditions of 
use as the natural-source drug or the waived product; there is a 
reasonable basis to conclude that the product would provide a 
comparable clinical effect to the natural-source drug or the waived 
product; and, for products containing large molecules (macromolecules), 
the active ingredients have the same principal molecular structural 
features and overall mechanism of action as the active ingredients in 
the natural-source drug or the waived product.
    Under proposed Sec.  300.60(b), an applicant must submit a waiver 
request with supporting documentation in an NDA or BLA, and an 
interested person must submit a waiver request as part of a submission 
under part 330.
    Existing regulations permit applicants to request waivers of any of 
the requirements under Sec. Sec.  314.50 through 314.81for NDAs, and 
for BLAs, and the information collections associated with such waiver 
requests generally are approved under existing control numbers. (See 
Sec.  314.90(a), waiver requests for drugs subject to NDAs and ANDAs 
(approved under OMB control number 0910-0001); and Sec.  600.90(a), 
waiver requests for products subject to BLAs (approved under OMB 
control number 0910-0308)).
    Concerning waiver requests submitted for a combination of active 
ingredients under consideration for inclusion in an OTC monograph in 
accordance with part 330, interested persons would submit such requests 
as a citizen petition in accordance with Sec.  10.30. FDA currently has 
OMB approval for the collection of information entitled ``General 
Administrative Procedures: Citizen Petitions; Petition for 
Reconsideration or Stay of Action; Advisory Opinions'' (OMB control 
number 0910-0183).
    Based on information provided in Section V of this preamble and in 
the Preliminary Regulatory Impact Analysis referenced in Section V, we 
estimate that FDA will receive approximately 15 waiver requests 
annually, and that each request will take approximately 50 hours to 
prepare and submit. The industry burden under the PRA for submitting 
waiver requests is calculated in Table 2:

                                                       Table 2--Estimated Annual Reporting Burden
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                         Number of                       Average burden
                                                                        Number of      responses per     Total annual     per response     Total Hours
                                                                       respondents       respondent       responses         (hours)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Waiver Requests under 21 CFR 300.60(b).............................              15                1               15               50              750
--------------------------------------------------------------------------------------------------------------------------------------------------------
There are no capital costs or operating and maintenance costs associated with this collection of information.

    In compliance with the PRA (44 U.S.C. 3507(d)), we have submitted 
the information collection requirements of this proposed rule to OMB 
for review. Interested persons are requested to send comments on this 
information collection by (see DATES) to the Office of Information and 
Regulatory Affairs, OMB. To ensure that comments on

[[Page 79793]]

information collection are received, OMB recommends that written 
comments be faxed to the Office of Information and Regulatory affairs, 
OMB, Attn: FDA Desk Officer, Fax: 202-395-7285, or emailed to 
oira_submission@ombeop.gov.

VII. Environmental Impact

    We have determined that under 21 CFR 25.30(h), this action is of a 
type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VIII. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed rule, if finalized, would not contain policies that would 
have substantial direct effects on the States, on the relationship 
between the National Government and the States, or on the distribution 
of power and responsibilities among the various levels of government. 
Accordingly, the Agency tentatively concludes that the proposed rule 
does not contain policies that have federalism implications as defined 
in the Executive order and, consequently, a federalism summary impact 
statement is not required.

IX. Proposed Effective Date

    We propose that any final rule that may issue based on this 
proposal become effective 30 days after the date of its publication in 
the Federal Register. Because we believe this proposed rule clarifies 
and codifies existing policy, we are proposing that this rulemaking, 
once finalized, would apply to all pending applications and citizen 
petitions.

X. Request for Comments

    Interested persons may submit either electronic comments regarding 
this document to http://www.regulations.gov or written comments to the 
Division of Dockets Management (see ADDRESSES). It is only necessary to 
send one set of comments. Identify comments with the docket number 
found in brackets in the heading of this document. Received comments 
may be seen in the Division of Dockets Management between 9 a.m. and 4 
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.

XI. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday, 
and are available electronically at http://www.regulations.gov.

1. Letter to G. Balkema, President, Bayer HealthCare, L.L.C., from 
D. Autor, Director, Office of Compliance, Center for Drug Evaluation 
and Research (CDER), re ``Bayer Aspirin With Heart Advantage'' 
(October 27, 2008), http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2008/ucm1048456.htm.
2. Letter to G. Balkema, President, Bayer HealthCare, L.L.C., from 
D. Autor, Director, Office of Compliance, CDER, re ``Bayer Women's 
Low Dose Aspirin + Calcium'' (October 27, 2008), http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2008/ucm1048083.htm.
3. Letter to R. McDonald, President and CEO, Procter & Gamble, from 
D. Autor, Director, Office of Compliance, CDER, re ``VICKS DayQuil 
Plus Vitamin C'' and ``VICKS NyQuil Plus Vitamin C'' (October 29, 
2009), http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2009/ucm188361.htm.
4. Letter to J. Ascher, President and CEO, B.F. Ascher & Co., Inc., 
from D. Horowitz, Acting Director, Office of Compliance, CDER, re 
``Melagesic PM Caplets'' (October 16, 2001), http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/UCM166379.pdf.
5. Letter to K. Irwin, President and CEO, Omni Neutraceuticals, 
Inc., from D. Horowitz, Acting Director, Office of Compliance, CDER, 
re ``Inholtra Joint Pain Caplets and Inholtra Joint Pain Plus'' 
(October 16, 2001).
6. ``Fixed Dose Combinations, Co-Packaged Drug Products, and Single-
Entity Versions of Previously Approved Antiretrovirals for the 
Treatment of HIV,'' available at http://www.fda.gov/Drugs under 
``Guidances (Drugs),'' http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/UCM166378.pdf.
7. ``Efficacy Studies to Support Marketing of Fibrin Sealant 
Products Manufactured for Commercial Use,'' available at http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm.
8. Food and Drug Administration, Full Disclosure of Preliminary 
Regulatory Impact Analysis, Initial Regulatory Flexibility Analysis, 
and Unfunded Mandates Reform Act Analysis on Regulations on Fixed-
Combination and Co-packaged Drugs and Combinations of Active 
Ingredients Under Consideration for Inclusion in an Over-the-Counter 
(OTC) Monograph Proposed Rule.

List of Subjects

21 CFR Part 300

    Drugs, Prescription drugs.

21 CFR Part 330

    Over-the-counter drugs.

21 CFR Part 610

    Biologics, Labeling, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and 
Public Health Service Act and under authority delegated to the 
Commissioner of Food and Drugs, FDA proposes to amend 21 CFR parts 300, 
330, and 610 as follows:

PART 300--GENERAL

0
1. The authority citation for 21 CFR part 300 is revised to read as 
follows:

    Authority: 21 U.S.C. 331, 351, 352, 355, 360b, 361, 371; 42 
U.S.C. 262.

0
2. Revise subpart B to read as follows:

Subpart B--Fixed-Combination and Co-Packaged Drugs and Combinations 
of Active Ingredients Under Consideration for Inclusion in an Over-
the-Counter (OTC) Monograph

Sec.
300.50 Definitions.
300.51 Applicability.
300.53 Requirements.
300.55 Combining one or more active ingredients with a natural-
source drug, a waived product, or a combination already included in 
an OTC monograph.
300.60 Waiver.

Sec.  300.50  Definitions.

    As used in this part:
    Active ingredient means any component that is intended to furnish 
pharmacological activity or other direct effect in the diagnosis, cure, 
mitigation, treatment, or prevention of disease, or to affect the 
structure or any function of the body of man or other animals. The term 
includes those components that may undergo chemical change in the 
manufacture of the drug product and be present in the drug product in a 
modified form intended to furnish the specified activity or effect.
    Applicant means any person who, to obtain approval of a fixed-
combination or co-packaged drug, submits a new drug application under 
section 505 of the Federal Food, Drug, and Cosmetic Act or a biologics 
license application under section 351 of the Public Health Service Act.
    Botanical raw material means a fresh or physically processed 
material derived from a single part of a single species of plant, or a 
fresh or physically processed alga or macroscopic fungus that has not

[[Page 79794]]

been genetically modified using recombinant DNA technology or any other 
process that deliberately changes the genome.
    Co-packaged drug is a product that contains two or more separate 
drugs in their final dosage forms that are intended to be used together 
for a common or related therapeutic purpose and that are contained in a 
single package or unit.
    Drug has the same meaning given this term in section 201(g) of the 
Federal Food, Drug, and Cosmetic Act and includes biological products 
as defined in section 351 of the Public Health Service Act that also 
meet the definition of ``drug'' in section 201(g) of the Federal Food, 
Drug and Cosmetic Act (21 U.S.C. 321(g)), but does not include any 
product that meets the definition of device under section 201(h) of the 
Federal Food, Drug, and Cosmetic Act.
    Fixed-combination drug means a drug in which two or more active 
ingredients are combined at a fixed dosage in a single dosage form. 
Natural-source drugs are not included under the definition of ``fixed-
combination drug'' unless those drugs are used as ingredients in 
combination with other ingredients in a single dosage form.
    Fungal raw material means a physically processed culture of a 
single-cell or multicellular organism, including yeasts, molds, and 
smut.
    Interested person means, with regard to a combination of two or 
more active ingredients under consideration for inclusion in an OTC 
monograph, any person who makes a submission under part 330 of this 
chapter regarding safety or effectiveness.
    Natural-source drug means a drug composed of one single animal, 
botanical, prokaryotic, fungal, or viral raw material, or derived from 
one such material using a manufacturing process that involves only 
physical steps (e.g., solvent extraction, condensation, column 
purification) and does not involve a chemical reaction (other than 
esterification or viral or bacterial inactivation) that would modify 
the covalent bonds of any substance in the original material. The 
composition of a natural-source drug may be adjusted for the purpose of 
assuring quality, but may not be changed in a way that would affect the 
product's activity (e.g., by selectively increasing or decreasing the 
concentration of particular active ingredients (for drugs that are 
biological products) or active moieties (for drugs that are not 
biological products)).
    Prokaryotic raw material means a physically processed culture of 
bacteria or other cellular organism lacking a true nucleus and nuclear 
membrane.
    Rational concurrent therapy means medically appropriate treatment 
for a patient population that is defined in the drug's labeling. That 
is, the defined patient population can benefit from all of the active 
ingredients at the specific doses present, given for a similar duration 
of treatment, and not be adversely affected by receiving them in 
combination.
    Single animal raw material means a single organ, human cell, 
tissue, and cellular- and tissue-based product, or bodily fluid 
collected from any human or nonhuman animal species that has not been 
genetically modified using recombinant DNA technology or any other 
process that deliberately changes the genome. A drug that is derived 
from an invertebrate animal species (including multiple parts or all of 
an invertebrate animal) may be considered a single animal raw material.
    Viral raw material means a minimally processed culture of a virus. 
The virus in culture may exist in nature or may have been attenuated or 
inactivated through selection or by physical and/or chemical means or 
recombinant technologies.
    Waived product means an approved product or a combination of active 
ingredients that has been generally recognized as safe and effective 
and included in an OTC monograph for which a waiver has been granted 
under Sec.  300.60.

Sec.  300.51  Applicability.

    This subpart applies to both prescription and OTC fixed-combination 
and co-packaged drugs that are subject to approval under a new drug 
application under section 505 of the Federal Food, Drug, and Cosmetic 
Act, or a biologics license application under section 351 of the Public 
Health Service Act, and to combinations of active ingredients under 
consideration for inclusion in an OTC monograph in accordance with part 
330 of this chapter. It does not apply to natural-source drugs unless 
those drugs are used as ingredients in combination with other 
ingredients in a single dosage form.

Sec.  300.53  Requirements.

    (a) Combinations of active ingredients under consideration for 
inclusion in an OTC monograph and fixed-combination and co-packaged 
drugs (collectively referred to in this section as ``the combination'') 
must meet the following requirements:
    (1) Each active ingredient makes a contribution to the effect(s) of 
the combination, enhances the safety or effectiveness of an active 
ingredient, or minimizes the potential for abuse of an active 
ingredient; and
    (2) The dosage of each active ingredient (amount, frequency of 
administration, and duration of use) is such that the combination is 
safe and effective and provides rational concurrent therapy.
    (b) Applicants and interested persons must:
    (1) State the intended use of each active ingredient in the 
combination; and
    (2) Submit sufficient evidence to demonstrate that the combination 
meets the requirements in paragraph (a) of this section, including 
evidence demonstrating the contribution of each active ingredient to 
the effect(s) of the combination. The amount and types of data and 
information needed to demonstrate such a contribution may vary and may 
include some or all of the following: Data from adequate and well-
controlled clinical trials, clinical pharmacology data, in vitro and 
animal model data, a basis for concluding there is a plausible 
pharmacologic rationale for the combination, and other relevant 
information.
    (c) The statement and evidence specified in paragraph (b) of this 
section must be included in a new drug application under section 505 of 
the Federal Food, Drug, and Cosmetic Act, a biologics license 
application under section 351 of the Public Health Service Act, or a 
submission under part 330 of this chapter to support inclusion of a 
combination in an OTC monograph.

Sec.  300.55  Combining one or more active ingredients with a natural-
source drug product or a waived product.

    For combinations not already described in an OTC monograph or for 
proposed fixed-combination and co-packaged drugs:
    (a) When a natural-source drug is combined with any other active 
ingredient, the natural-source drug will be considered a single active 
ingredient for the purposes of fulfilling the requirements of Sec.  
300.53.
    (b) When a natural-source drug is combined with one or more 
additional natural-source drugs, each natural-source drug in the 
combination will be considered a single active ingredient for the 
purposes of fulfilling the requirements of Sec.  300.53.
    (c) When a waived product is combined with any other active 
ingredient, the waived product will be considered a single active 
ingredient for the purposes of fulfilling the requirements of Sec.  
300.53.

[[Page 79795]]

Sec.  300.60  Waiver.

    (a) FDA may, at the request of an applicant or interested person or 
on its own initiative, grant a waiver of any of the requirements under 
Sec.  300.53 with regard to a fixed-combination or co-packaged drug 
that is the subject of a pending application under section 505 of the 
Federal Food, Drug, and Cosmetic Act or section 351 of the Public 
Health Service Act, or a combination of active ingredients under 
consideration for inclusion in an OTC monograph in accordance with part 
330 of this chapter, if it finds one of the following:
    (1)(i) There is a reasonable rationale for the combination of the 
individual active ingredients; and
    (ii) Compliance with any of the requirements of Sec.  300.53 would 
be infeasible or medically unreasonable or unethical; or
    (2) The product contains all or a subset of the known components in 
the same ratio as a natural-source drug or a waived product provided 
the product is intended for the same conditions of use as the natural-
source drug or the waived product; there is a reasonable basis to 
conclude that the product would provide a comparable clinical effect to 
the natural-source drug or the waived product; and, for products 
containing large molecules (macromolecules), the macromolecules have 
the same principal molecular structural features and overall mechanism 
of action as those in the natural-source drug or the waived product.
    (b) If an applicant wishes to request a waiver, it must submit the 
waiver request with supporting documentation in an application under 
section 505 of the Federal Food, Drug, and Cosmetic Act or section 351 
of the Public Health Service Act. If an interested person wishes to 
request a waiver, the waiver request must be submitted as part of a 
submission under part 330 of this chapter.
    (c) FDA will provide appropriate written notice when the Agency 
grants a waiver on its own initiative, or grants or denies a request 
for a waiver. Fixed-combination and co-packaged drugs and combinations 
of active ingredients under consideration for inclusion in an OTC 
monograph for which a waiver is granted must still meet all other 
applicable requirements under section 505 of the Federal Food, Drug, 
and Cosmetic Act, section 351 of the Public Health Service Act, or 
Sec.  330.10(a)(4) of this chapter, as appropriate.

PART 330--OVER-THE-COUNTER (OTC) HUMAN DRUGS WHICH ARE GENERALLY 
RECOGNIZED AS SAFE AND EFFECTIVE AND NOT MISBRANDED

0
3. The authority citation for 21 CFR part 330 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

0
4. Amend Sec.  330.10 by revising paragraph (a)(4)(iv) to read as 
follows:

Sec.  330.10  Procedures for classifying OTC drugs as generally 
recognized as safe and effective and not misbranded, and for 
establishing monographs.

* * * * *
    (a) * * *
    (4) * * *
    (iv) A combination of two or more active ingredients that are 
individually classified as drugs generally recognized as safe and 
effective in accordance with the requirements of Sec.  300.53 of this 
chapter must meet the requirements of subpart B of part 300 of this 
chapter to be generally recognized as safe and effective and included 
in an OTC monograph. If such combination is granted a waiver under 
Sec.  300.60 of this chapter, it must still meet all other applicable 
requirements of this subparagraph to be generally recognized as safe 
and effective and included in an OTC monograph. Unless otherwise 
specified in the applicable OTC monograph(s), combinations of active 
ingredients that are included in an OTC monograph may be used in either 
fixed-combination or co-packaged drugs.
* * * * *

PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS

0
5. The authority citation for 21 CFR part 610 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 
360d, 360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a, 
264.

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6. Amend Sec.  610.17 by revising the section heading, designating the 
existing paragraph as paragraph (a), and by adding paragraph (b) to 
read as follows:

Sec.  610.17  Permissible fixed-combinations.

    (a) * * *
    (b) A drug product subject to approval under section 351 of the 
Public Health Service Act may not be combined with another drug product 
except in accordance with subpart B of part 300 of this chapter.

    Dated: December 17, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-32246 Filed 12-22-15; 8:45 am]
BILLING CODE 4164-01-P