[Federal Register Volume 80, Number 246 (Wednesday, December 23, 2015)]
[Proposed Rules]
[Pages 79776-79795]
[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.

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,
<EMAIL_ADDRESS>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,
<EMAIL_ADDRESS>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.

    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

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

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

(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,

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

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

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

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

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

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).

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.

    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

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.

                                    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

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

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:<PHONE_NUMBER>, or emailed to
<EMAIL_ADDRESS>
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