[Federal Register Volume 72, Number 184 (Monday, September 24, 2007)]
[Proposed Rules]
[Pages 54226-54230]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-18714]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-308P]


Technical Amendment to Listing in Schedule III of Approved Drug 
Products Containing Tetrahydrocannabinols

AGENCY: Drug Enforcement Administration (DEA), Department of Justice.

ACTION: Notice of Proposed Rulemaking.

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SUMMARY: Under the current schedules of controlled substances in the 
DEA regulations, among the substances listed in schedule III is a 
synthetic isomer of tetrahydrocannabinols (THC) contained in a specific 
formulation of a drug product approved by the U.S. Food and Drug 
Administration (FDA). As currently written, the DEA regulation would 
not necessarily include drug products approved by the FDA under section 
505(j) of the Food, Drug, and Cosmetic Act (FDCA) (21 U.S.C. 355) 
(commonly referred to as generic drugs) that cite the drug product 
currently listed in schedule III as the reference listed drug. DEA is 
hereby proposing to modify the regulation so that certain generic drug 
products are also included in the schedule III listing.

DATES: Written comments must be postmarked, and electronic comments 
must be sent, on or before November 23, 2007.

[[Page 54227]]


ADDRESSES: Please submit comments, identified by ``Docket No. DEA-
308,'' by one of the following methods:
    1. Regular mail: Deputy Administrator, Drug Enforcement 
Administration, Washington, DC 20537, Attention: DEA Federal Register 
Representative/ODL.
    2. Express mail: DEA Headquarters, Attention: DEA Federal Register 
Representative/ODL, 2401 Jefferson-Davis Highway, Alexandria, VA 22301.
    3. E-mail comments directly to agency: 
[email protected].
    4. Federal eRulemaking portal: http://www.regulations.gov. Follow 
the on-line instructions for submitting comments.
    Posting of Public Comments: Please note that all comments received 
are considered part of the public record and made available for public 
inspection online at http://www.regulations.gov and in the Drug 
Enforcement Administration's public docket. Such information includes 
personal identifying information (such as your name, address, etc.) 
voluntarily submitted by the commenter.
    If you want to submit personal identifying information (such as 
your name, address, etc.) as part of your comment, but do not want it 
to be posted online or made available in the public docket, you must 
include the phrase ``PERSONAL IDENTIFYING INFORMATION'' in the first 
paragraph of your comment. You must also place all the personal 
identifying information you do not want posted online or made available 
in the public docket in the first paragraph of your comment and 
identify what information you want redacted.
    If you want to submit confidential business information as part of 
your comment, but do not want it to be posted online or made available 
in the public docket, you must include the phrase ``CONFIDENTIAL 
BUSINESS INFORMATION'' in the first paragraph of your comment. You must 
also prominently identify confidential business information to be 
redacted within the comment. If a comment has so much confidential 
business information that it cannot be effectively redacted, all or 
part of that comment may not be posted online or made available in the 
public docket.
    Personal identifying information and confidential business 
information identified and located as set forth above will be redacted 
and the comment, in redacted form, will be posted online and placed in 
the Drug Enforcement Administration's public docket file. If you wish 
to inspect the agency's public docket file in person by appointment, 
please see the ``FOR FURTHER INFORMATION'' paragraph.

FOR FURTHER INFORMATION CONTACT: Christine A. Sannerud, Ph.D., Chief, 
Drug and Chemical Evaluation Section, Office of Diversion Control, Drug 
Enforcement Administration, Washington, DC 20537; Telephone: (202) 307-
7183.

SUPPLEMENTARY INFORMATION:

I. Summary

    Under the Controlled Substances Act (CSA), the schedules of 
controlled substances are published on an updated basis in the DEA 
regulations.\1\ Currently, one of the substances listed in schedule III 
is the following: ``Dronabinol (synthetic) in sesame oil and 
encapsulated in a soft gelatin capsule in a U.S. Food and Drug 
Administration approved product.'' \2\ This describes the drug product 
marketed under the brand name Marinol. As explained below, it is 
possible that generic versions of Marinol could be approved by the FDA 
yet not fit within the same schedule III listing as Marinol. The rule 
being proposed here would correct this situation so that certain 
generic versions of Marinol that might be approved by the FDA in the 
future will be in the same schedule as Marinol.
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    \1\ 21 U.S.C. 812(a), (c) and n. 1.
    \2\ 21 CFR 1308.13(g)(1).
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II. Detailed Explanation

Background

    Dronabinol is a name of a particular isomer of a class of chemicals 
known as tetrahydrocannabinols (THC). Specifically, dronabinol is the 
United States Adopted Name (USAN) for the (-)-isomer of [Delta]\9\-
(trans)-tetrahydrocannabinol [(-)-[Delta]\9\-(trans)-THC], which is 
believed to be the major psychoactive component of the cannabis plant 
(marijuana).
    At present, Marinol is the only drug product containing any form of 
THC that has been approved for marketing by the FDA.\3\ Accordingly, 
THC, as a general category, is listed in schedule I of the CSA,\4\ 
while dronabinol contained in the Marinol formulation is listed 
separately in schedule III. Any other formulation containing dronabinol 
(or any other isomer of THC) remains a schedule I controlled 
substance.\5\
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    \3\ The FDA approved Marinol in 1985 for the treatment of nausea 
and vomiting associated with cancer chemotherapy. In 1992, the FDA 
expanded Marinol's approved indications to include the treatment of 
anorexia associated with weight loss in patients with AIDS.
    \4\ 21 U.S.C. 812(c), Schedule I(c)(17). Schedule I contains 
those controlled substances with ``no currently accepted medical use 
in treatment in the United States'' and ``a lack of accepted safety 
for use * * * under medical supervision.'' 21 U.S.C. 812(b)(1).
    \5\ The introductory language to schedule I(c) states that any 
material, compound, mixture, or preparation that contains any of the 
substances listed in schedule I(c) (including 
``tetrahydrocannabinols'') is a schedule I controlled substance 
``[u]nless specifically excepted or unless listed in another 
schedule.'' The only material, compound, mixture, or preparation 
that contains THC but is listed in another schedule is the Marinol 
formulation, which is listed in schedule III.
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    The current wording of the Marinol formulation in schedule III (21 
CFR 1308.13(g)(1)) was added to the DEA regulations in 1986, when the 
substance was transferred from schedule I to schedule II after the FDA 
approved Marinol for marketing.\6\ The wording of this listing was not 
specific to Marinol and thereby could include any generic product 
meeting that description that might be approved by the FDA in the 
future. However, at the time the regulation was promulgated, DEA did 
not anticipate the possibility that a generic formulation could be 
developed that did not fit precisely the wording of the listing that 
currently appears in schedule III.
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    \6\ 51 FR 17476 (May 13, 1986). DEA subsequently transferred the 
FDA-approved Marinol formulation from schedule II to schedule III. 
64 FR 35928 (July 2, 1999).
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    Recently, firms have submitted to FDA abbreviated new drug 
applications (ANDA) for their proposed generic versions of Marinol. As 
these ANDAs remain pending with the FDA, the precise nature of these 
formulations is not available for public disclosure. However, these 
formulations might differ from the Marinol formulation currently listed 
in schedule III. Nonetheless, the firms that have submitted the ANDAs 
assert that their formulations would meet the approval requirements 
under 21 U.S.C. 355(j), because, among other things, they have the same 
active ingredient, strength, dosage form, and route of administration 
as Marinol, and are bioequivalent to Marinol. Products are 
bioequivalent if there is no significant difference in the rate and 
extent to which the active ingredient or active moiety becomes 
available at the site of drug action. 21 CFR 320.1. There is no 
requirement under 21 U.S.C. 355(j), or FDA's implementing regulations, 
that solid oral dosage forms such as capsules that are proposed for 
approval in ANDAs contain the same inactive ingredients as the listed 
drug referenced. Thus, for example, a sponsor of an ANDA referencing 
Marinol could propose for approval a capsule formulated with an 
inactive ingredient other than sesame oil. The generic drug,

[[Page 54228]]

therefore, would not fall within the scope of the current regulation.
    This situation, in which a generic version of a drug would not 
necessarily fall within the schedule for the referenced listed drug, is 
unique among the CSA schedules in the following respect. The Marinol 
formulation listed in schedule III is the only listing in the schedules 
that has the effect of excluding potential generic versions of the 
brand name formulation.\7\ As indicated above, this came about because 
DEA did not anticipate that other drug products could be approved by 
FDA that did not fit the description that was included in the 
schedules. Moreover, Congress structured the CSA so that there would be 
no distinction--for scheduling purposes--between brand name drug 
products and their generic equivalents. The rule being proposed here 
would ensure that this aspect of the CSA holds true for generic drug 
products approved under 21 U.S.C. 355(j) that reference Marinol as the 
listed drug.
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    \7\ Generally, substances are listed in the CSA schedules based 
on their chemical classification, rather than any drug product 
formulation in which they might appear. Because of this, there have 
been no other situations in which a slight variation between the 
brand name drug formulation and the generic drug formulation was 
consequential for scheduling purposes.
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    In addition, 21 U.S.C. 355(j)(2)(C) permits applicants to petition 
FDA for approval in an ANDA for a drug product that may differ from the 
listed drug in certain specified ways, if clinical studies are not 
necessary to establish the safety and effectiveness of the drug 
product. Among the types of differences permitted is a change in dosage 
form. This proposed rule would amend the description in Schedule III to 
include products referencing Marinol that are either capsules or 
tablets and that otherwise meet the approval requirements in 21 U.S.C. 
355(j).

The CSA Scheduling Structure

    To understand the legal justification for the rule being proposed 
here, the scheduling scheme established by Congress under the CSA must 
first be considered. One court has succinctly summarized this scheme as 
follows:

    The [CSA] sets forth initial schedules of drugs and controlled 
substances in 21 U.S.C. 812(c). However, Congress established 
procedures for adding or removing substances from the schedules 
(control or decontrol), or to transfer a drug or substance between 
schedules (reschedule). 21 U.S.C. 811(a). This responsibility is 
assigned to the Attorney General in consultation with the Secretary 
of Health and Human Services (``HHS''). Id. Sec.  811(b). The 
Attorney General has delegated his functions to the Administrator of 
the DEA. 28 CFR 0.100(b). Current schedules are published at 21 CFR 
1308.11-1308.15.
    There are three methods by which the DEA may initiate rulemaking 
proceedings to revise the schedules: (1) By the DEA's own motion; 
(2) at the request of HHS; (3) on the petition of any interested 
party. 21 U.S.C. 811(a); 21 CFR 1308.43(a). Before initiating 
rulemaking proceedings, the DEA must request a scientific and 
medical evaluation from HHS and a recommendation. The statute 
requires the DEA and HHS to consider eight factors with respect to 
the drug or controlled substance. 21 U.S.C. 811(b), (c). These 
factors are:
    (1) Its actual or relative potential for abuse.
    (2) Scientific evidence of its pharmacological effect, if known.
    (3) The state of current scientific knowledge regarding the drug 
or other substance.
    (4) Its history and current pattern of abuse.
    (5) The scope, duration, and significance of abuse.
    (6) What, if any, risk there is to the public health.
    (7) Its psychic or physiological dependence liability.
    (8) Whether the substance is an immediate precursor of a 
substance already controlled under this subchapter.
    21 U.S.C. 811(c). Although the recommendations of HHS are 
binding on the DEA as to scientific and medical considerations 
involved in the eight-factor test, the ultimate decision as to 
whether to initiate rulemaking proceedings to reschedule a 
controlled substance is made by the DEA. See id. Sec.  811(a), (b).

Gettman v. DEA, 290 F.3d 430, 432 (DC Cir. 2002).

    The FDA plays an important role within HHS in the development of 
the HHS medical and scientific determinations that bear on eight-factor 
analyses referred to above (required under section 811(c) for 
scheduling decisions). Thus, when it comes to newly developed drug 
products that contain controlled substances, FDA makes medical and 
scientific determinations for purposes of both the Food Drug and 
Cosmetic Act (in connection with decisions on whether to approve drugs 
for marketing) and the CSA (in connection with scheduling decisions). 
As explained below, the eight-factor analysis can be expected to yield 
the same conclusions with respect to a brand name drug product and 
certain generic drugs referencing that product that meet the approval 
requirements under 21 U.S.C. 355(j).

The ANDA Approval Process

    The Drug Price Competition and Patent Term Restoration Act of 1984 
(known as the ``Hatch-Waxman Amendments''), codified at 21 U.S.C. 355, 
360cc, and 35 U.S.C. 156, 271, 282, permits the submission of ANDAs for 
approval of generic versions of approved drug products. 21 U.S.C. 
355(j). The ANDA process shortens the time and effort needed for 
approval by, among other things, allowing the applicant to demonstrate 
its product's bioequivalence to a drug already approved under a New 
Drug Application (NDA) (the ``listed'' drug) rather than having to 
reproduce the safety and effectiveness data for that drug. If an ANDA 
applicant establishes that its proposed drug product has the same 
active ingredient, strength, dosage form, route of administration, 
labeling, and conditions of use as a listed drug, and that it is 
bioequivalent to that drug, the applicant can rely on FDA's previous 
finding that the listed drug is safe and effective. See id. \8\ Once 
approved, an ANDA sponsor may manufacture and market the generic drug 
to provide a safe, effective, and low cost alternative to the American 
public.
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    \8\ See also Approved Drug Products with Therapeutic Equivalence 
Evaluations (commonly known as the ``Orange Book''), Intro. at p. 
vi, (27th ed.).
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    The majority of drugs approved under 21 U.S.C. 355(j) are 
therapeutically equivalent to the listed drug they reference. This 
means that the generic drug and the referenced innovator drug are in 
the same dosage form, contain identical amounts of the active 
ingredient, and are bioequivalent. Therapeutic equivalents can be 
expected to have the same clinical effect and safety profile when 
administered to patients under the conditions specified in the 
labeling.
    The key point, for purposes of the rule being proposed here, is 
that the generic drug can be substituted for the innovator drug with 
the full expectation that the generic drug will produce the same 
clinical effect and safety profile as the innovator drug. Consequently, 
for CSA scheduling purposes, the eight-factor analysis conducted by the 
FDA and DEA under 21 U.S.C. 811(c) would necessarily result in the same 
scheduling determination for an approved generic drug product as for 
the innovator drug to which the generic drug is a therapeutic 
equivalent. This is because, in conducting the eight-factor analysis, 
the FDA and DEA would be examining precisely the same medical, 
scientific, and abuse data for the generic drug product as would be 
considered for the innovator drug. The same would be true of the 
innovator drug and a drug product approved pursuant to a petition under 
21 U.S.C. 355(j)(2)(C), where the drug approved in the ANDA differs 
from the listed drug only because it is a tablet and the listed drug is 
a capsule.

[[Page 54229]]

    As noted earlier, these considerations never previously arose for 
any other controlled substance because the regulation citing the 
Marinol formulation is the only scheduling regulation that is drug-
product-formulation-specific and thereby (inadvertently) excludes 
potential generic versions.\9\ This unintended result is not consistent 
with the structure and purposes of the CSA, which generally lists 
categories of substances in the schedules, rather than product 
formulations.\10\ Thus, by ensuring that generic versions of the 
Marinol formulation which might be approved by the FDA in the future 
are in the same schedule as Marinol, the rule being proposed here would 
make the DEA regulations more consistent with the structure and 
purposes of the CSA. Moreover, because--from a scientific perspective--
the eight-factor analysis for such generic products would lead to the 
same results as with the innovator drug, this proposed rule would 
eliminate the needless expenditure of agency resources to conduct 
redundant eight-factor analyses. (HHS and DEA have already conducted 
the eight-factor analysis for the Marinol formulation.\11\) In a 
similar vein, this proposed rule will eliminate an unnecessary 
administrative hurdle that could otherwise stand in the way of allowing 
generic drugs to reach the American consumer without undue delay.
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    \9\ When Congress enacted the CSA in 1970, it scheduled codeine 
and certain other opiates in three different schedules depending on 
their respective concentrations. See 21 U.S.C. 812(c), schedule 
II(a)(1), schedule III(d), and schedule V. However, this 
differential scheduling for opiates does not specify drug product 
formulation in a manner that would result in a generic version of an 
opiate drug product being scheduled separately from the innovator 
drug.
    \10\ See note 9.
    \11\ The last eight-factor analysis for Marinol was completed in 
1998, as part of the process of transferring it from schedule II to 
schedule III. 64 FR 35928 (July 2, 1999).
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    Finally, for additional clarity, the proposed rule will amend 21 
CFR 1308.13(g)(1) to change the phrase ``U.S. Food and Drug 
Administration approved product'' to ``drug product approved for 
marketing by the U.S. Food and Drug Administration.''

Note Regarding This Proposed Scheduling Action

    In accordance with the provisions of the Controlled Substances Act 
(21 U.S.C. 811(a)), this action is a formal rulemaking ``on the record 
after opportunity for a hearing.'' Such proceedings are conducted 
pursuant to the provisions of the Administrative Procedure Act (5 
U.S.C. 556 and 557). Interested persons are invited to submit their 
comments, objections or requests for a hearing with regard to this 
proposal. Persons wishing to request a hearing should note that such 
requests must be written and manually signed; requests for a hearing 
will not be accepted via electronic means. Requests for a hearing 
should be made in accordance with 21 CFR 1308.44 and should state, with 
particularity, the issues concerning which the person desires to be 
heard. All correspondence regarding this matter should be submitted to 
the DEA using the address information provided above.

Regulatory Certifications

Regulatory Flexibility Act

    The Deputy Administrator hereby certifies that this rulemaking has 
been drafted in accordance with the Regulatory Flexibility Act (5 
U.S.C. 601-612), has reviewed this regulation, and by approving it 
certifies that this regulation will not have a significant economic 
impact on a substantial number of small entities. DEA is hereby 
proposing to modify the listing of the Marinol formulation in schedule 
III so that certain generic drug products are also included in that 
listing. Further, this proposed rule will eliminate an unnecessary 
administrative hurdle that could otherwise stand in the way of allowing 
generic drugs to reach the American consumer without undue delay.

Executive Order 12866

    In accordance with the provisions of the CSA (21 U.S.C. 811(a)), 
this action is a formal rulemaking ``on the record after opportunity 
for a hearing.'' Such proceedings are conducted pursuant to the 
provisions of 5 U.S.C. 556 and 557 and, as such, are exempt from review 
by the Office of Management and Budget pursuant to Executive Order 
12866, 3(d)(1).

Executive Order 12988

    This regulation meets the applicable standards set forth in 
Sections 3(a) and 3(b)(2) of Executive Order 12988 Civil Justice 
Reform.

Executive Order 13132

    This rulemaking does not preempt or modify any provision of state 
law; nor does it impose enforcement responsibilities on any state; nor 
does it diminish the power of any state to enforce its own laws. 
Accordingly, this rulemaking does not have federalism implications 
warranting the application of Executive Order 13132.

Unfunded Mandates Reform Act of 1995

    This rule will not result in the expenditure by State, local, and 
tribal governments, in the aggregate, or by the private sector, of 
$120,000,000 or more (adjusted for inflation) in any one year, and will 
not significantly or uniquely affect small governments. Therefore, no 
actions were deemed necessary under the provisions of the Unfunded 
Mandates Reform Act of 1995.

Congressional Review Act

    This rule is not a major rule as defined by Section 804 of the 
Small Business Regulatory Enforcement Fairness Act (Congressional 
Review Act). This rule will not result in an annual effect on the 
economy of $100,000,000 or more; a major increase in costs or prices; 
or significant adverse effects on competition, employment, investment, 
productivity, innovation, or on the ability of United States-based 
companies to compete with foreign-based companies in domestic and 
export markets.

List of Subjects in 21 CFR Part 1308

    Administrative practice and procedure, Drug traffic control, 
Narcotics, Prescription drugs.

    Pursuant to the authority vested in the Attorney General under 
sections 201, 202, and 501(b) of the CSA (21 U.S.C. 811, 812, and 
871(b)), delegated to the Administrator and Deputy Administrator 
pursuant to section 501(a) (21 U.S.C. 871(a)) and as specified in 28 
CFR 0.100 and 0.104, and Appendix to Subpart R, sec. 12, the Deputy 
Administrator hereby orders that Title 21 of the Code of Federal 
Regulations, Part 1308, is proposed to be amended as follows:

PART 1308--SCHEDULES OF CONTROLLED SUBSTANCES

    1. The authority citation for part 1308 continues to read as 
follows:

    Authority: 21 U.S.C. 811, 812, 871(b), unless otherwise noted.

    2. Section 1308.13 is proposed to be amended by revising paragraph 
(g) to read as follows:


Sec.  1308.13  Schedule III.

* * * * *
    (g) Hallucinogenic substances.
    (1)(i) Dronabinol in sesame oil and encapsulated in a soft gelatin 
capsule in a drug product approved for marketing by the U.S. Food and 
Drug Administration (FDA)--7369
    (ii) Any drug product in tablet or capsule form containing natural 
dronabinol (derived from the cannabis

[[Page 54230]]

plant) or synthetic dronabinol (produced from synthetic materials) for 
which an abbreviated new drug application (ANDA) has been approved by 
the FDA under section 505(j) of the Federal Food, Drug, and Cosmetic 
Act which references as its listed drug the drug product referred to in 
the preceding paragraph (g)(1)(i) of this section.--7369


[Some other names for Dronabinol: (6a R-trans)-6a,7,8,10a-tetrahydro-
6,6,9-trimethyl-3-pentyl-6 H-dibenzo [b,d]pyran-1-ol] or (-)-delta-9-
(trans)-tetrahydrocannabinol]
    (2) [Reserved]

    Dated: September 17, 2007.
Michele M. Leonhart,
Deputy Administrator.
 [FR Doc. E7-18714 Filed 9-21-07; 8:45 am]
BILLING CODE 4410-09-P