Schedules of Controlled Substances: Removal of Naloxegol From Control, 64349-64353 [2014-25685]

Download as PDF Federal Register / Vol. 79, No. 209 / Wednesday, October 29, 2014 / Proposed Rules service information related to this AD, contact Costruzioni Aeronautiche Tecnam Airworthiness Office, Via Maiorise–81043 Capua (CE) Italy; telephone: +39 0823 997538; fax: +39 0823 622899; email: technical.support@tecnam.com; Internet: http://www.tecnam.com/Customer-Care/ Service-Bulletins.aspx. You may review this referenced service information at the FAA, Small Airplane Directorate, 901 Locust, Kansas City, Missouri 64106. For information on the availability of this material at the FAA, call (816) 329–4148. Issued in Kansas City, Missouri, on October 22, 2014. Earl Lawrence, Manager, Small Airplane Directorate, Aircraft Certification Service. [FR Doc. 2014–25740 Filed 10–28–14; 8:45 am] BILLING CODE 4910–13–P DEPARTMENT OF JUSTICE Drug Enforcement Admininstration 21 CFR Part 1308 [Docket No. DEA–400] Schedules of Controlled Substances: Removal of Naloxegol From Control Drug Enforcement Administration, Department of Justice. ACTION: Notice of proposed rulemaking. AGENCY: The Drug Enforcement Administration (DEA) proposes to remove naloxegol ((5a,6 a)-17-allyl-6((20-hydroxy-3,6,9,12,15,18hexaoxaicos-1-yl)oxy)-4,5epoxymorphinon-3,14-diol) and its salts from the schedules of the Controlled Substances Act (CSA). This scheduling action is pursuant to the CSA which requires that such actions be made on the record after opportunity for a hearing through formal rulemaking. Naloxegol is currently a schedule II controlled substance because it can be derived from opium alkaloids. This action would remove the regulatory controls and administrative, civil, and criminal sanctions applicable to controlled substances, including those specific to schedule II controlled substances, on persons who handle (manufacture, distribute, reverse distribute, dispense, conduct research, import, export, or conduct chemical analysis) or propose to handle naloxegol. DATES: Interested persons may file written comments on this proposal in accordance with 21 CFR 1308.43(g). Electronic comments must be submitted, and written comments must be postmarked, on or before November 28, 2014. Commenters should be aware rmajette on DSK2TPTVN1PROD with PROPOSALS SUMMARY: VerDate Sep<11>2014 13:59 Oct 28, 2014 Jkt 235001 that the electronic Federal Docket Management System will not accept comments after 11:59 p.m. Eastern Time on the last day of the comment period. Interested persons, defined at 21 CFR 1300.01 as those ‘‘adversely affected or aggrieved by any rule or proposed rule issuable pursuant to section 201 of the Act (21 U.S.C. 811)’’, may file a request for hearing or waiver of participation pursuant to 21 CFR 1308.44 and in accordance with 21 CFR 1316.45, 1316.47, 1316.48, or 1316.49, as applicable. Requests for hearing, notices of appearance, and waivers of an opportunity for a hearing or to participate in a hearing must be received on or before November 28, 2014. ADDRESSES: To ensure proper handling of comments, please reference ‘‘Docket No. DEA–400’’ on all correspondence, including any attachments. • Electronic comments: The DEA encourages that all comments be submitted through the Federal eRulemaking Portal, which provides the ability to type short comments directly into the comment field on the Web page or to attach a file for lengthier comments. Please go to http:// www.regulations.gov and follow the online instructions at that site for submitting comments. Upon completion of your submission you will receive a Comment Tracking Number for your comment. Please be aware that submitted comments are not instantaneously available for public view on Regulations.gov. If you have received a comment tracking number, your comment has been successfully submitted and there is no need to resubmit the same comment. • Paper comments: Paper comments that duplicate an electronic submission are not necessary and are discouraged. Should you wish to mail a comment in lieu of an electronic format, it should be sent via regular or express mail to: Drug Enforcement Administration, Attention: DEA Federal Register Representative/ ODXL, 8701 Morrissette Drive, Springfield, Virginia 22152. • Hearing requests: All requests for hearing and waivers of participation must be sent to: Drug Enforcement Administration, Attn: Hearing Clerk/LJ, 8701 Morrissette Drive, Springfield, Virginia 22152. FOR FURTHER INFORMATION CONTACT: Imelda L. Paredes, Office of Diversion Control, Drug Enforcement Administration; Mailing Address: 8701Morrissette Drive, Springfield, Virginia 22152; Telephone: (202) 598– 6812. SUPPLEMENTARY INFORMATION: PO 00000 Frm 00015 Fmt 4702 Sfmt 4702 64349 Posting of Public Comments Please note that all comments received in response to this docket are considered part of the public record. They will, unless reasonable cause is given, be made available by the DEA for public inspection online at http:// www.regulations.gov. Such information includes personal identifying information (such as your name, address, etc.) voluntarily submitted by the commenter. The Freedom of Information Act (FOIA) applies to all comments received. 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 made publicly available, you must include the phrase ‘‘PERSONAL IDENTIFYING INFORMATION’’ in the first paragraph of your comment. You must also place the personal identifying information you do not want made publicly available 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 made publicly available, 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. Comments containing personal identifying information and confidential business information identified as directed above will generally be made publicly available in redacted form. If a comment has so much confidential business information or personal identifying information that it cannot be effectively redacted, all or part of that comment may not be made publicly available. Comments posted to http:// www.regulations.gov may include any personal identifying information (such as name, address, and phone number) included in the text of your electronic submission that is not identified as directed above as confidential. An electronic copy of this document and supplemental information to this proposed rule are available at http:// www.regulations.gov for easy reference. The DEA specifically solicits written comments regarding the DEA’s economic analysis of the impact of these proposed changes. The DEA requests that commenters provide detailed descriptions in their comments of any expected economic impacts, especially to small entities. Commenters should provide empirical data to illustrate the nature and scope of such impact. E:\FR\FM\29OCP1.SGM 29OCP1 64350 Federal Register / Vol. 79, No. 209 / Wednesday, October 29, 2014 / Proposed Rules Request for Hearing, Notice of Appearance at or Waiver of Participation in Hearing Pursuant to 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 (APA) (5 U.S.C. 551–559). 21 CFR 1308.41– 1308.45, and 21 CFR part 1316 subpart D. In accordance with 21 CFR 1308.44 (a)–(c), requests for hearing, notices of appearance, and waivers of an opportunity for a hearing or to participate in a hearing may be submitted only by interested persons, defined as those ‘‘adversely affected or aggrieved by any rule or proposed rule issuable pursuant to section 201 of the Act (21 U.S.C. 811).’’ 21 CFR 1300.01. Such requests or notices must conform to the requirements of 21 CFR 1308.44 (a) or (b), and 1316.47 or 1316.48, as applicable, and include a statement of the interest of the person in the proceeding and the objections or issues, if any, concerning which the person desires to be heard. Any waiver must conform to the requirements of 21 CFR 1308.44(c) and 1316.49, including a written statement regarding the interested person’s position on the matters of fact and law involved in any hearing. Please note that pursuant to 21 U.S.C. 811(a), the purpose and subject matter of a hearing is restricted to ‘‘(A) find[ing] that such drug or other substance has a potential for abuse, and (B) mak[ing] with respect to such drug or other substance the findings prescribed by subsection (b) of section 812 of this title for the schedule in which such drug is to be placed * * *.’’ All requests for hearing and waivers of participation must be sent to the DEA using the address information above, on or before the date specified above. rmajette on DSK2TPTVN1PROD with PROPOSALS Legal Authority The Drug Enforcement Administration (DEA) implements and enforces titles II and III of the Comprehensive Drug Abuse Prevention and Control Act of 1970, as amended. 21 U.S.C. 801–971. Titles II and III are referred to as the ‘‘Controlled Substances Act’’ and the ‘‘Controlled Substances Import and Export Act,’’ respectively, but they are collectively referred to as the ‘‘Controlled Substances Act’’ or the ‘‘CSA’’ for the purposes of this action. The DEA publishes the implementing regulations for these statutes in title 21 of the Code of Federal Regulations (CFR), parts 1300 to 1321. The CSA and its implementing VerDate Sep<11>2014 13:59 Oct 28, 2014 Jkt 235001 regulations are designed to prevent, detect, and eliminate the diversion of controlled substances and listed chemicals into the illicit market while providing for the legitimate medical, scientific, research, and industrial needs of the United States. Controlled substances have the potential for abuse and dependence and are controlled to protect the public health and safety. Under the CSA, each controlled substance is classified into one of five schedules based upon its potential for abuse, its currently accepted medical use in treatment in the United States, and the degree of dependence the drug or other substance may cause. 21 U.S.C. 812. The initial schedules of controlled substances established by Congress are found at 21 U.S.C. 812(c) and the current list of scheduled substances is published at 21 CFR part 1308. 21 U.S.C. 812(a). Pursuant to 21 U.S.C. 811(a)(2), the Attorney General may, by rule, ‘‘remove any drug or other substance from the schedules if he finds that the drug or other substance does not meet the requirements for inclusion in any schedule.’’ The Attorney General has delegated scheduling authority under 21 U.S.C. 811 to the Administrator of the DEA, 28 CFR 0.100, who in turn has redelegated that authority to the Deputy Administrator of the DEA, 28 CFR part 0, appendix to subpart R. The CSA provides that proceedings for the issuance, amendment, or repeal of the scheduling of any drug or other substance may be initiated by the Attorney General (1) on his own motion, (2) at the request of the Secretary of the Department of Health and Human Services (HHS),1 or (3) on the petition of any interested party. 21 U.S.C. 811(a). This action was initiated by a petition to remove naloxegol from the list of scheduled controlled substances of the CSA, and is supported by, inter alia, a recommendation from the Assistant Secretary of the HHS and an evaluation of all relevant data by the DEA. This action would remove the regulatory controls and administrative, civil, and criminal sanctions applicable to controlled substances, including those specific to schedule II controlled 1 As discussed in a memorandum of understanding entered into by the Food and Drug Administration (FDA) and the National Institute on Drug Abuse (NIDA), the FDA acts as the lead agency within the HHS in carrying out the Secretary’s scheduling responsibilities under the CSA, with the concurrence of NIDA. 50 FR 9518, Mar. 8, 1985. The Secretary of the HHS has delegated to the Assistant Secretary for Health of the HHS the authority to make domestic drug scheduling recommendations. 58 FR 35460, July 1, 1993. PO 00000 Frm 00016 Fmt 4702 Sfmt 4702 substances, on persons who handle or propose to handle naloxegol. Background Naloxegol, or PEG-naloxol, is a new molecular entity and is a polyethylene glycolyated (PEGylated) derivative of naloxone. Its chemical names are (5a,6 a)-17-allyl-6-((20-hydroxy3,6,9,12,15,18-hexaoxaicos-1-yl)oxy)4,5-epoxymorphinon-3,14-diol or alpha6mPEG7–O-naloxol. Naloxegol is an antagonist predominantly of peripheral mu opioid receptors. The Food and Drug Administration (FDA) approved naloxegol for marketing on September 16, 2014, under the brand name MovantikTM.2 It is indicated for the treatment of opioid-induced constipation (OIC) in adults with chronic non-cancer pain. Gastrointestinal adverse events (AEs) effects are commonly experienced by chronic users of opioid analgesics. Opioids delay gastric emptying and intestinal transport, which over time leads to debilitating constipation. OIC is caused by activation of the mu opioid receptor in the GI tract. Proposed Determination To Decontrol Naloxegol Pursuant to 21 U.S.C. 811(a), proceedings to issue, amend, or repeal scheduling actions may be initiated on the petition of any interested party. In accordance with 21 CFR 1308.43, the DEA received a petition from the drug sponsor dated March 22, 2012, requesting that the DEA amend 21 CFR 1308.12(b)(1) to exclude naloxegol as a schedule II controlled substance. The petitioner stated that naloxegol is a mu opioid receptor antagonist without mu opioid agonist or partial agonist properties. In accordance with 21 CFR 1308.43(c), the DEA accepted the petition for filing on October 1, 2012. Pursuant to 21 U.S.C. 811(b), the DEA gathered the necessary data on naloxegol and on February 7, 2013, forwarded to the HHS the data with the sponsor’s petition along with a request for a scientific and medical evaluation and the HHS’s recommendation as to whether or not naloxegol should be removed from the list of controlled substances. According to the HHS, the sponsor submitted a New Drug Application (NDA) for naloxegol on September 16, 2013. Based on the NDA, the HHS summarized that naloxegol is an antagonist of peripheral opioid receptors for the treatment of OIC. 2 http://www.accessdata.fda.gov/scripts/cder/ drugsatfda/index.cfm?fuseaction=Search .DrugDetails (last accessed Sept. 26, 2014). E:\FR\FM\29OCP1.SGM 29OCP1 Federal Register / Vol. 79, No. 209 / Wednesday, October 29, 2014 / Proposed Rules On August 8, 2014, the HHS provided to the DEA a scientific and medical evaluation document prepared by the FDA entitled ‘‘Basis for the Recommendation to Decontrol Naloxegol and its Salts from Schedule II of the Controlled Substances Act.’’ Pursuant to 21 U.S.C. 811(b), this document contained an eight-factor analysis of naloxegol as a new drug, along with the HHS’s recommendation to remove naloxegol from the schedules of the CSA. In response, the DEA reviewed the scientific and medical evaluation and scheduling recommendation provided by the HHS, and all other relevant data, and completed its own eight-factor review document on naloxegol pursuant to 21 U.S.C. 811(c). Included below is a brief summary of each factor as analyzed by the HHS and DEA, and as considered by the DEA in this proposal to remove naloxegol from the schedules of the CSA. Please note that both the DEA and HHS analyses are available in their entirety under ‘‘Supporting and Related Material’’ of the public docket for this rule at http:// www.regulations.gov under docket number DEA–400. rmajette on DSK2TPTVN1PROD with PROPOSALS 1. The Drug’s Actual or Relative Potential for Abuse Naloxegol is a new molecular entity that has not been marketed in the United States or in any other country. As such, there is no information available regarding actual abuse of naloxegol. However, scientific studies show that naloxegol does not demonstrate a potential for abuse. Naloxegol is a conjugation of polyethylene glycol (PEG) to naloxone. Naloxegol binds to mu, delta, and kappa opioid receptors and acts as an antagonist at these receptors. PEGylation of naloxone decreases the capacity of the substance to cross the blood-brain barrier, limiting the availability of naloxegol to peripheral opioid receptors (Diego et al., 2011; HHS review). Due to naloxegol being an antagonist at the three opioid receptors, mu, delta, and kappa, the HHS asserts that naloxegol does not have opioid agonist properties. Further, in abuse liability studies in animals, naloxegol did not produce responses seen with morphine administration. In clinical studies, the reports show that naloxegol does not produce euphoria or abuse potential related AEs. For example, the HHS stated that ‘‘[n]aloxegol (30 to 1,000 mg/kg) produced less than 20% morphine-appropriate responding at any dose, which meets criteria for a ‘no- VerDate Sep<11>2014 13:59 Oct 28, 2014 Jkt 235001 drug’ interoceptive cue.’’ 3 Therefore, naloxegol does not demonstrate a potential for abuse. 2. Scientific Evidence of the Drug’s Pharmacological Effects, if Known Binding studies showed that naloxegol does not bind significantly (>50% inhibition) to other molecular central nervous system (CNS) receptors, including dopamine, serotonin, glutamate, a-aminobutyric acid (GABA), sigma, acetylcholine, norepinephrine, cannabinoid, histamine, and monoamine transporters. Toxicological studies in rats and dogs did not produce behavioral signs of abuse potential, e.g. increased or decreased motor behavior, decreased body weight, or food intake. In two analgesia models in rodents, naloxegol did not produce any analgesic effects, demonstrating the lack of mu opioid receptor activation. Naloxegol was also tested in both analgesia models for its potency in reversing morphineinduced (subcutaneous or intravenous, 1–32 mg/kg) analgesia. Naloxegol did not fully reverse the analgesia produced by morphine, demonstrating that antagonistic actions of naloxegol were predominantly at the peripheral opioid receptor and not at the opioid receptors in the CNS. According to the HHS, oral naloxegol (12.5 and 25 mg/day) did precipitate opioid withdrawal in patients receiving opioids for pain management in the Phase 2/3 clinical trials. The incidence of withdrawal was low, the symptoms of opioid withdrawals occurred in patients taking naloxegol (2%) compared to placebo (<1%). It occurred with a higher incidence in patients receiving naloxegol (3%) at the higher dose (25 mg/day) than those receiving the 12.5 mg/day dose (1%). The HHS asserts that the withdrawal symptoms reported did not always meet the criteria of a clinically meaningful opioid withdrawal syndrome. 3. The State of Current Scientific Knowledge Regarding the Drug or Other Substance Naloxegol is known as (5a,6a)-17allyl-6-((20-hydroxy-3,6,9,12,15,18hexaoxaicos-1-yl)oxy)-4,5epoxymorphinon-3,14-diol and also as alpha-6mPEG7–O-naloxol. The CAS number is 854601–70–0. The molecular formula of naloxegol is C34H53NO11 and the molecular weight is 651.8 g/ mol. It is a white to off-white powder and is soluble in aqueous solvents over 3 U.S. Food and Drug Administration, Department of Health and Human Services, Basis for the Recommendation to Decontrol Naloxegol and Its Salts from Schedule II of the Controlled Substances Act (2014), p. 6. PO 00000 Frm 00017 Fmt 4702 Sfmt 4702 64351 a pH range of 1 to 7.5. Naloxegol is synthesized in a five-step process from naloxone hydrochloride, an opioid antagonist derived from thebaine. Naloxegol (25 mg/day) is rapidly absorbed following oral administration in healthy volunteers. Maximum plasma concentrations were reached in 1.5 to 2 hours. The plasma half-life (t 1⁄2) is 7 to 9 hours, with a maximal plasma concentration (Cmax) of 45 ng/ml. In a drug distribution study in humans with radiolabeled naloxegol, the highest levels of radioactivity were in the liver and kidneys. The elimination t 1⁄2 of naloxegol is rapid, with majority being eliminated within 24-hours post-dose. 4. Its History and Current Pattern of Abuse According to HHS, there has been no evidence of abuse-related signals from the human clinical trials. Naloxegol is a mu opioid antagonist, which as a class does not have abuse potential. 5. The Scope, Duration, and Significance of Abuse There have been no reports of abuse of naloxegol. According to the National Forensic Laboratory Information System (NFLIS) 4 and the System to Retrieve Information from Drug Evidence (STRIDE),5 there have been no reports of naloxegol seizures from 2010 to the present. 6. What, if Any, Risk There Is to the Public Health According to the HHS, naloxegol is well-tolerated and safe at the therapeutic doses of 12.5 mg and 25 mg. Preclinical and clinical studies showed no evidence of potential for abuse of naloxegol and thus there is little public health risk from naloxegol. 4 The National Forensic Laboratory Information System (NFLIS) is a program of the DEA, Office of Diversion Control. NFLIS systematically collects drug identification results and associated information from drug cases submitted to and analyzed by State and local forensic laboratories. NFLIS represents an important resource in monitoring illicit drug abuse and trafficking, including the diversion of legally manufactured pharmaceuticals into illegal markets. NFLIS is a comprehensive information system that includes data from forensic laboratories that handle approximately 90% of an estimated 1.0 million distinct annual State and local drug analysis cases. NFLIS includes drug chemistry results from completed analyses only. While NFLIS data is not direct evidence of abuse, it can lead to an inference that a drug has been diverted and abused. See 76 FR 77330, 77332, Dec. 12, 2011. 5 The System to Retrieve Information from Drug Evidence (STRIDE) is a database of drug exhibits sent to DEA laboratories for analysis. Exhibits from the database are from the DEA, other federal agencies, and local law enforcement agencies. E:\FR\FM\29OCP1.SGM 29OCP1 64352 Federal Register / Vol. 79, No. 209 / Wednesday, October 29, 2014 / Proposed Rules 7. Its Psychic or Physiological Dependence Liability responsibilities among the various levels of government. There were no symptoms of physical dependence in a naloxegol physical dependence liability study in rats. The HHS also mentioned that the lack of naloxegol self-administration by animals is consistent with a lack of psychic dependence liability. Executive Order 13175 This rule does not have tribal implications warranting the application of Executive Order 13175. This rule does not have substantial direct effects on one or more Indian tribes, on the relationship between the Federal Government and Indian tribes, or on the distribution of power and responsibilities between the Federal Government and Indian tribes. 8. Whether the Substance is an Immediate Precursor of a Substance Already Controlled Under the CSA Naloxegol is not considered an immediate precursor of any controlled substance. Conclusion Based on consideration of the scientific and medical evaluation and accompanying recommendation of the HHS, and based on the DEA’s consideration of its own eight-factor analysis, the DEA finds that these facts and all relevant data demonstrate that naloxegol does not possess abuse or dependence potential. Accordingly, the DEA finds that naloxegol does not meet the requirements for inclusion in any schedule, and should be removed from control under the CSA. Regulatory Analyses Executive Orders 12866 and 15363 In accordance with 21 U.S.C. 811(a), this scheduling action is subject to formal rulemaking procedures done ‘‘on the record after opportunity for a hearing,’’ which are conducted pursuant to the provisions of 5 U.S.C. 556 and 557. The CSA sets forth the criteria for scheduling a drug or other substance. Such actions are exempt from review by the Office of Management and Budget (OMB) pursuant to section 3(d)(1) of Executive Order 12866 and the principles reaffirmed in Executive Order 13563. 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 to eliminate drafting errors and ambiguity, minimize litigation, provide a clear legal standard for affected conduct, and promote simplification and burden reduction. rmajette on DSK2TPTVN1PROD with PROPOSALS Executive Order 13132 This rulemaking does not have federalism implications warranting the application of Executive Order 13132. The rule does not have substantial direct effects on the States, on the relationship between the Federal Government and the States, or the distribution of power and VerDate Sep<11>2014 13:59 Oct 28, 2014 Jkt 235001 Regulatory Flexibility Act The Deputy Administrator, in accordance with the Regulatory Flexibility Act (5 U.S.C. 601–612) (RFA), has reviewed this proposed rule and by approving it certifies that it will not have a significant economic impact on a substantial number of small entities. The purpose of this rule is to remove naloxegol from the list of schedules of the CSA. This action will remove regulatory controls and administrative, civil, and criminal sanctions applicable to controlled substances for handlers and proposed handlers of naloxegol. Accordingly, it has the potential for some economic impact in the form of cost savings. Naloxegol is a new molecular entity and is not currently available or marketed in any country. According to publicly available information reviewed by the DEA, naloxegol is anticipated to enjoy patent protection for an extended period of time before generic equivalents may be manufactured and marketed in the United States. Although the number of manufacturers of naloxegol may initially be limited, there is potential for numerous handlers in various business activities, e.g., distributors, hospitals/clinics, pharmacies, practitioners, etc. If finalized, the proposed rule will affect all persons who would handle, or propose to handle, naloxegol. Due to the wide variety of unidentifiable and unquantifiable variables that potentially could influence the distribution and dispensing rates of new molecular entities, the DEA is unable to determine the number of entities and small entities which might handle naloxegol. However, the DEA estimates that all persons who would handle, or propose to handle naloxegol, are currently registered with the DEA to handle schedule II controlled substances. Therefore, the 1.5 million (1,469,418 as of September 2014) controlled substance registrations, representing approximately 426,714 entities, would be the maximum number of entities affected by this rule. The DEA estimates PO 00000 Frm 00018 Fmt 4702 Sfmt 4702 that 417,302 (97.8%) of 426,714 affected entities are ‘‘small entities’’ in accordance with the RFA and Small Business Administration size standards. The DEA estimates all controlled substances registrants handle both controlled and non-controlled substances and these registrants are expected to continue to handle naloxegol if the proposed rule were finalized. Additionally, since prospective naloxegol handlers are likely to handle other schedule II controlled substances, the cost savings they would receive as a result of the decontrol of naloxegol would be nominal. As naloxegol handlers continue to handle other scheduled II controlled substances, they will need to maintain their DEA registration and keep the same security and recordkeeping processes, equipment, and facilities in place and would experience only a nominal reduction in security, inventory, recordkeeping, and labeling costs. While the DEA does not have a basis to estimate the number of affected entities, the DEA estimates that the maximum number of affected entities is 426,714 of which 417,302 are estimated to be small entities. Since the affected entities are expected to handle other schedule II controlled substances and maintain security and recordkeeping facilities and processes consistent with schedule II controlled substances handling requirements, the DEA estimates any economic impact (cost savings) will be nominal. Because of these facts, this rule will not result in a significant economic impact on a substantial number of small entities. Unfunded Mandates Reform Act of 1995 On the basis of information contained in the ‘‘Regulatory Flexibility Act’’ section above, the DEA has determined and certifies pursuant to the Unfunded Mandates Reform Act of 1995 (UMRA), 2 U.S.C. 1501 et seq., that this action would not result in 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 for inflation) in any one year * * *.’’ Therefore, neither a Small Government Agency Plan nor any other action is required under provisions of UMRA. Paperwork Reduction Act This action does not impose a new collection of information requirement under the Paperwork Reduction Act, 44 U.S.C. 3501–3521. This action would not impose recordkeeping or reporting requirements on State or local governments, individuals, businesses, or E:\FR\FM\29OCP1.SGM 29OCP1 Federal Register / Vol. 79, No. 209 / Wednesday, October 29, 2014 / Proposed Rules organizations. An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB control number. List of Subjects in 21 CFR Part 1308 Administrative practice and procedure, Drug traffic control, Reporting and recordkeeping requirements. For the reasons set out above, 21 CFR part 1308 is proposed to be amended to read as follows: PART 1308—SCHEDULES OF CONTROLLED SUBSTANCES 1. The authority citation for 21 CFR part 1308 continues to read as follows: ■ Authority: 21 U.S.C. 811, 812, 871(b), unless otherwise noted. 2. In § 1308.12, amend the introductory text of paragraph (b)(1) by adding the word ‘‘naloxegol,’’ between ‘‘nalmefene,’’ and ‘‘naloxone,’’ to read as follows: ■ § 1308.12 Schedule II. (a) * * * (b) * * * (1) Opium and opiate, and any salt, compound, derivative, or preparation of opium or opiate excluding apomorphine, thebaine-derived butorphanol, dextrorphan, nalbuphine, nalmefene, naloxegol, naloxone, and naltrexone, and their respective salts, but including the following: * * * * * Dated: October 23, 2014. Thomas M. Harrigan, Deputy Administrator. [FR Doc. 2014–25685 Filed 10–28–14; 8:45 am] BILLING CODE 4410–09–P ENVIRONMENTAL PROTECTION AGENCY 40 CFR Part 52 [EPA–R09–OAR–2014–0696; FRL–9918–58– Region 9] Revisions to the California State Implementation Plan, Ventura County Air Pollution Control District Environmental Protection Agency (EPA). rmajette on DSK2TPTVN1PROD with PROPOSALS AGENCY: ACTION: Proposed rule. The Environmental Protection Agency (EPA) is proposing to approve a State Implementation Plan (SIP) revision submitted by California for the Ventura County Air Pollution Control District (VCAPCD or ‘‘the District’’) portion of the California SIP. The submitted SIP revision contains the District’s demonstration regarding Reasonably Available Control Technology (RACT) requirements for the 2008 8-hour ozone National Ambient Air Quality Standards (NAAQS). We are proposing to approve the submitted SIP revision under the Clean Air Act as amended in 1990 (CAA or the Act). We are taking comments on this proposal and plan to follow with a final action. DATES: Any comments must arrive by November 28, 2014. ADDRESSES: Submit comments, identified by docket number EPA–R09– OAR–2014–0696, by one of the following methods: 1. Federal eRulemaking Portal: www.regulations.gov. Follow the on-line instructions. 2. Email: steckel.andrew@epa.gov. 3. Mail or deliver: Andrew Steckel (Air-4), U.S. Environmental Protection Agency Region IX, 75 Hawthorne Street, San Francisco, CA 94105–3901. Instructions: All comments will be included in the public docket without change and may be made available online at www.regulations.gov, including any personal information provided, unless the comment includes Confidential Business Information (CBI) or other information whose disclosure is restricted by statute. Information that you consider CBI or otherwise protected should be clearly identified as such and should not be submitted through www.regulations.gov or email. www.regulations.gov is an ‘‘anonymous access’’ system, and EPA will not know your identity or contact information unless you provide it in the body of your comment. If you send email directly to EPA, your email address will be automatically captured and included as part of the public comment. If EPA cannot read your comment due to technical difficulties and cannot contact you for clarification, EPA may not be able to consider your comment. SUMMARY: 64353 Electronic files should avoid the use of special characters, any form of encryption, and be free of any defects or viruses. Docket: Generally, documents in the docket for this action are available electronically at www.regulations.gov and in hard copy at EPA Region IX, 75 Hawthorne Street, San Francisco, California. While all documents in the docket are listed at www.regulations.gov, some information may be publicly available only at the hard copy location (e.g., copyrighted material, large maps), and some may not be publicly available in either location (e.g., CBI). To inspect the hard copy materials, please schedule an appointment during normal business hours with the contact listed in the FOR FURTHER INFORMATION CONTACT section. FOR FURTHER INFORMATION CONTACT: Stanley Tong, EPA Region IX, (415) 947–4122, tong.stanley@epa.gov. SUPPLEMENTARY INFORMATION: Throughout this document, ‘‘we,’’ ‘‘us’’ and ‘‘our’’ refer to EPA. Table of Contents I. The State’s Submittal A. What document did the State submit? B. Are there other versions of document? C. What is the purpose of the RACT SIP submission? II. EPA’s Evaluation and Proposed Action A. How is EPA evaluating the RACT SIP submission? B. Does the RACT SIP submission meet the evaluation criteria? C. EPA’s Recommendation To Strengthen the RACT SIP D. Proposed Action and Public Comment III. Statutory and Executive Order Reviews I. The State’s Submittal A. What document did the State submit? Table 1 lists the document addressed by this proposal with the date that it was adopted by the local air agency and submitted by the California Air Resources Board. TABLE 1—SUBMITTED DOCUMENT Local agency Document VCAPCD ................... 2014 Reasonably Available Control Technology (RACT) State Implementation Plan (SIP) Revision (‘‘2014 RACT SIP’’). VerDate Sep<11>2014 13:59 Oct 28, 2014 Jkt 235001 PO 00000 Frm 00019 Fmt 4702 Adopted Sfmt 4702 E:\FR\FM\29OCP1.SGM 29OCP1 6/10/14 Submitted 7/18/14

Agencies

[Federal Register Volume 79, Number 209 (Wednesday, October 29, 2014)]
[Proposed Rules]
[Pages 64349-64353]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-25685]


=======================================================================
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DEPARTMENT OF JUSTICE

Drug Enforcement Admininstration

21 CFR Part 1308

[Docket No. DEA-400]


Schedules of Controlled Substances: Removal of Naloxegol From 
Control

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Notice of proposed rulemaking.

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SUMMARY: The Drug Enforcement Administration (DEA) proposes to remove 
naloxegol ((5[alpha],6 [alpha])-17-allyl-6-((20-hydroxy-3,6,9,12,15,18-
hexaoxaicos-1-yl)oxy)-4,5-epoxymorphinon-3,14-diol) and its salts from 
the schedules of the Controlled Substances Act (CSA). This scheduling 
action is pursuant to the CSA which requires that such actions be made 
on the record after opportunity for a hearing through formal 
rulemaking. Naloxegol is currently a schedule II controlled substance 
because it can be derived from opium alkaloids. This action would 
remove the regulatory controls and administrative, civil, and criminal 
sanctions applicable to controlled substances, including those specific 
to schedule II controlled substances, on persons who handle 
(manufacture, distribute, reverse distribute, dispense, conduct 
research, import, export, or conduct chemical analysis) or propose to 
handle naloxegol.

DATES: Interested persons may file written comments on this proposal in 
accordance with 21 CFR 1308.43(g). Electronic comments must be 
submitted, and written comments must be postmarked, on or before 
November 28, 2014. Commenters should be aware that the electronic 
Federal Docket Management System will not accept comments after 11:59 
p.m. Eastern Time on the last day of the comment period.
    Interested persons, defined at 21 CFR 1300.01 as those ``adversely 
affected or aggrieved by any rule or proposed rule issuable pursuant to 
section 201 of the Act (21 U.S.C. 811)'', may file a request for 
hearing or waiver of participation pursuant to 21 CFR 1308.44 and in 
accordance with 21 CFR 1316.45, 1316.47, 1316.48, or 1316.49, as 
applicable. Requests for hearing, notices of appearance, and waivers of 
an opportunity for a hearing or to participate in a hearing must be 
received on or before November 28, 2014.

ADDRESSES: To ensure proper handling of comments, please reference 
``Docket No. DEA-400'' on all correspondence, including any 
attachments.
     Electronic comments: The DEA encourages that all comments 
be submitted through the Federal eRulemaking Portal, which provides the 
ability to type short comments directly into the comment field on the 
Web page or to attach a file for lengthier comments. Please go to 
http://www.regulations.gov and follow the online instructions at that 
site for submitting comments. Upon completion of your submission you 
will receive a Comment Tracking Number for your comment. Please be 
aware that submitted comments are not instantaneously available for 
public view on Regulations.gov. If you have received a comment tracking 
number, your comment has been successfully submitted and there is no 
need to resubmit the same comment.
     Paper comments: Paper comments that duplicate an 
electronic submission are not necessary and are discouraged. Should you 
wish to mail a comment in lieu of an electronic format, it should be 
sent via regular or express mail to: Drug Enforcement Administration, 
Attention: DEA Federal Register Representative/ODXL, 8701 Morrissette 
Drive, Springfield, Virginia 22152.
     Hearing requests: All requests for hearing and waivers of 
participation must be sent to: Drug Enforcement Administration, Attn: 
Hearing Clerk/LJ, 8701 Morrissette Drive, Springfield, Virginia 22152.

FOR FURTHER INFORMATION CONTACT: Imelda L. Paredes, Office of Diversion 
Control, Drug Enforcement Administration; Mailing Address: 
8701Morrissette Drive, Springfield, Virginia 22152; Telephone: (202) 
598-6812.

SUPPLEMENTARY INFORMATION:

Posting of Public Comments

    Please note that all comments received in response to this docket 
are considered part of the public record. They will, unless reasonable 
cause is given, be made available by the DEA for public inspection 
online at http://www.regulations.gov. Such information includes 
personal identifying information (such as your name, address, etc.) 
voluntarily submitted by the commenter. The Freedom of Information Act 
(FOIA) applies to all comments received. 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 made publicly available, you 
must include the phrase ``PERSONAL IDENTIFYING INFORMATION'' in the 
first paragraph of your comment. You must also place the personal 
identifying information you do not want made publicly available 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 made publicly available, 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.
    Comments containing personal identifying information and 
confidential business information identified as directed above will 
generally be made publicly available in redacted form. If a comment has 
so much confidential business information or personal identifying 
information that it cannot be effectively redacted, all or part of that 
comment may not be made publicly available. Comments posted to http://www.regulations.gov may include any personal identifying information 
(such as name, address, and phone number) included in the text of your 
electronic submission that is not identified as directed above as 
confidential.
    An electronic copy of this document and supplemental information to 
this proposed rule are available at http://www.regulations.gov for easy 
reference. The DEA specifically solicits written comments regarding the 
DEA's economic analysis of the impact of these proposed changes. The 
DEA requests that commenters provide detailed descriptions in their 
comments of any expected economic impacts, especially to small 
entities. Commenters should provide empirical data to illustrate the 
nature and scope of such impact.

[[Page 64350]]

Request for Hearing, Notice of Appearance at or Waiver of Participation 
in Hearing

    Pursuant to 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 (APA) (5 U.S.C. 551-559). 21 CFR 1308.41-1308.45, and 21 CFR part 
1316 subpart D. In accordance with 21 CFR 1308.44 (a)-(c), requests for 
hearing, notices of appearance, and waivers of an opportunity for a 
hearing or to participate in a hearing may be submitted only by 
interested persons, defined as those ``adversely affected or aggrieved 
by any rule or proposed rule issuable pursuant to section 201 of the 
Act (21 U.S.C. 811).'' 21 CFR 1300.01. Such requests or notices must 
conform to the requirements of 21 CFR 1308.44 (a) or (b), and 1316.47 
or 1316.48, as applicable, and include a statement of the interest of 
the person in the proceeding and the objections or issues, if any, 
concerning which the person desires to be heard. Any waiver must 
conform to the requirements of 21 CFR 1308.44(c) and 1316.49, including 
a written statement regarding the interested person's position on the 
matters of fact and law involved in any hearing.
    Please note that pursuant to 21 U.S.C. 811(a), the purpose and 
subject matter of a hearing is restricted to ``(A) find[ing] that such 
drug or other substance has a potential for abuse, and (B) mak[ing] 
with respect to such drug or other substance the findings prescribed by 
subsection (b) of section 812 of this title for the schedule in which 
such drug is to be placed * * *.'' All requests for hearing and waivers 
of participation must be sent to the DEA using the address information 
above, on or before the date specified above.

Legal Authority

    The Drug Enforcement Administration (DEA) implements and enforces 
titles II and III of the Comprehensive Drug Abuse Prevention and 
Control Act of 1970, as amended. 21 U.S.C. 801-971. Titles II and III 
are referred to as the ``Controlled Substances Act'' and the 
``Controlled Substances Import and Export Act,'' respectively, but they 
are collectively referred to as the ``Controlled Substances Act'' or 
the ``CSA'' for the purposes of this action. The DEA publishes the 
implementing regulations for these statutes in title 21 of the Code of 
Federal Regulations (CFR), parts 1300 to 1321. The CSA and its 
implementing regulations are designed to prevent, detect, and eliminate 
the diversion of controlled substances and listed chemicals into the 
illicit market while providing for the legitimate medical, scientific, 
research, and industrial needs of the United States. Controlled 
substances have the potential for abuse and dependence and are 
controlled to protect the public health and safety.
    Under the CSA, each controlled substance is classified into one of 
five schedules based upon its potential for abuse, its currently 
accepted medical use in treatment in the United States, and the degree 
of dependence the drug or other substance may cause. 21 U.S.C. 812. The 
initial schedules of controlled substances established by Congress are 
found at 21 U.S.C. 812(c) and the current list of scheduled substances 
is published at 21 CFR part 1308. 21 U.S.C. 812(a).
    Pursuant to 21 U.S.C. 811(a)(2), the Attorney General may, by rule, 
``remove any drug or other substance from the schedules if he finds 
that the drug or other substance does not meet the requirements for 
inclusion in any schedule.'' The Attorney General has delegated 
scheduling authority under 21 U.S.C. 811 to the Administrator of the 
DEA, 28 CFR 0.100, who in turn has redelegated that authority to the 
Deputy Administrator of the DEA, 28 CFR part 0, appendix to subpart R.
    The CSA provides that proceedings for the issuance, amendment, or 
repeal of the scheduling of any drug or other substance may be 
initiated by the Attorney General (1) on his own motion, (2) at the 
request of the Secretary of the Department of Health and Human Services 
(HHS),\1\ or (3) on the petition of any interested party. 21 U.S.C. 
811(a). This action was initiated by a petition to remove naloxegol 
from the list of scheduled controlled substances of the CSA, and is 
supported by, inter alia, a recommendation from the Assistant Secretary 
of the HHS and an evaluation of all relevant data by the DEA. This 
action would remove the regulatory controls and administrative, civil, 
and criminal sanctions applicable to controlled substances, including 
those specific to schedule II controlled substances, on persons who 
handle or propose to handle naloxegol.
---------------------------------------------------------------------------

    \1\ As discussed in a memorandum of understanding entered into 
by the Food and Drug Administration (FDA) and the National Institute 
on Drug Abuse (NIDA), the FDA acts as the lead agency within the HHS 
in carrying out the Secretary's scheduling responsibilities under 
the CSA, with the concurrence of NIDA. 50 FR 9518, Mar. 8, 1985. The 
Secretary of the HHS has delegated to the Assistant Secretary for 
Health of the HHS the authority to make domestic drug scheduling 
recommendations. 58 FR 35460, July 1, 1993.
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Background

    Naloxegol, or PEG-naloxol, is a new molecular entity and is a 
polyethylene glycolyated (PEGylated) derivative of naloxone. Its 
chemical names are (5[alpha],6 [alpha])-17-allyl-6-((20-hydroxy-
3,6,9,12,15,18-hexaoxaicos-1-yl)oxy)-4,5-epoxymorphinon-3,14-diol or 
alpha-6mPEG7-O-naloxol. Naloxegol is an antagonist predominantly of 
peripheral mu opioid receptors. The Food and Drug Administration (FDA) 
approved naloxegol for marketing on September 16, 2014, under the brand 
name MovantikTM.\2\ It is indicated for the treatment of 
opioid-induced constipation (OIC) in adults with chronic non-cancer 
pain. Gastrointestinal adverse events (AEs) effects are commonly 
experienced by chronic users of opioid analgesics. Opioids delay 
gastric emptying and intestinal transport, which over time leads to 
debilitating constipation. OIC is caused by activation of the mu opioid 
receptor in the GI tract.
---------------------------------------------------------------------------

    \2\ http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search .DrugDetails (last accessed Sept. 26, 
2014).
---------------------------------------------------------------------------

Proposed Determination To Decontrol Naloxegol

    Pursuant to 21 U.S.C. 811(a), proceedings to issue, amend, or 
repeal scheduling actions may be initiated on the petition of any 
interested party. In accordance with 21 CFR 1308.43, the DEA received a 
petition from the drug sponsor dated March 22, 2012, requesting that 
the DEA amend 21 CFR 1308.12(b)(1) to exclude naloxegol as a schedule 
II controlled substance. The petitioner stated that naloxegol is a mu 
opioid receptor antagonist without mu opioid agonist or partial agonist 
properties. In accordance with 21 CFR 1308.43(c), the DEA accepted the 
petition for filing on October 1, 2012.
    Pursuant to 21 U.S.C. 811(b), the DEA gathered the necessary data 
on naloxegol and on February 7, 2013, forwarded to the HHS the data 
with the sponsor's petition along with a request for a scientific and 
medical evaluation and the HHS's recommendation as to whether or not 
naloxegol should be removed from the list of controlled substances. 
According to the HHS, the sponsor submitted a New Drug Application 
(NDA) for naloxegol on September 16, 2013. Based on the NDA, the HHS 
summarized that naloxegol is an antagonist of peripheral opioid 
receptors for the treatment of OIC.

[[Page 64351]]

    On August 8, 2014, the HHS provided to the DEA a scientific and 
medical evaluation document prepared by the FDA entitled ``Basis for 
the Recommendation to Decontrol Naloxegol and its Salts from Schedule 
II of the Controlled Substances Act.'' Pursuant to 21 U.S.C. 811(b), 
this document contained an eight-factor analysis of naloxegol as a new 
drug, along with the HHS's recommendation to remove naloxegol from the 
schedules of the CSA.
    In response, the DEA reviewed the scientific and medical evaluation 
and scheduling recommendation provided by the HHS, and all other 
relevant data, and completed its own eight-factor review document on 
naloxegol pursuant to 21 U.S.C. 811(c). Included below is a brief 
summary of each factor as analyzed by the HHS and DEA, and as 
considered by the DEA in this proposal to remove naloxegol from the 
schedules of the CSA. Please note that both the DEA and HHS analyses 
are available in their entirety under ``Supporting and Related 
Material'' of the public docket for this rule at http://www.regulations.gov under docket number DEA-400.

1. The Drug's Actual or Relative Potential for Abuse

    Naloxegol is a new molecular entity that has not been marketed in 
the United States or in any other country. As such, there is no 
information available regarding actual abuse of naloxegol. However, 
scientific studies show that naloxegol does not demonstrate a potential 
for abuse.
    Naloxegol is a conjugation of polyethylene glycol (PEG) to 
naloxone. Naloxegol binds to mu, delta, and kappa opioid receptors and 
acts as an antagonist at these receptors. PEGylation of naloxone 
decreases the capacity of the substance to cross the blood-brain 
barrier, limiting the availability of naloxegol to peripheral opioid 
receptors (Diego et al., 2011; HHS review). Due to naloxegol being an 
antagonist at the three opioid receptors, mu, delta, and kappa, the HHS 
asserts that naloxegol does not have opioid agonist properties. 
Further, in abuse liability studies in animals, naloxegol did not 
produce responses seen with morphine administration. In clinical 
studies, the reports show that naloxegol does not produce euphoria or 
abuse potential related AEs. For example, the HHS stated that 
``[n]aloxegol (30 to 1,000 mg/kg) produced less than 20% morphine-
appropriate responding at any dose, which meets criteria for a `no-
drug' interoceptive cue.'' \3\ Therefore, naloxegol does not 
demonstrate a potential for abuse.
---------------------------------------------------------------------------

    \3\ U.S. Food and Drug Administration, Department of Health and 
Human Services, Basis for the Recommendation to Decontrol Naloxegol 
and Its Salts from Schedule II of the Controlled Substances Act 
(2014), p. 6.
---------------------------------------------------------------------------

2. Scientific Evidence of the Drug's Pharmacological Effects, if Known

    Binding studies showed that naloxegol does not bind significantly 
(>50% inhibition) to other molecular central nervous system (CNS) 
receptors, including dopamine, serotonin, glutamate, [alpha]-
aminobutyric acid (GABA), sigma, acetylcholine, norepinephrine, 
cannabinoid, histamine, and monoamine transporters. Toxicological 
studies in rats and dogs did not produce behavioral signs of abuse 
potential, e.g. increased or decreased motor behavior, decreased body 
weight, or food intake. In two analgesia models in rodents, naloxegol 
did not produce any analgesic effects, demonstrating the lack of mu 
opioid receptor activation. Naloxegol was also tested in both analgesia 
models for its potency in reversing morphine-induced (subcutaneous or 
intravenous, 1-32 mg/kg) analgesia. Naloxegol did not fully reverse the 
analgesia produced by morphine, demonstrating that antagonistic actions 
of naloxegol were predominantly at the peripheral opioid receptor and 
not at the opioid receptors in the CNS. According to the HHS, oral 
naloxegol (12.5 and 25 mg/day) did precipitate opioid withdrawal in 
patients receiving opioids for pain management in the Phase 2/3 
clinical trials. The incidence of withdrawal was low, the symptoms of 
opioid withdrawals occurred in patients taking naloxegol (2%) compared 
to placebo (<1%). It occurred with a higher incidence in patients 
receiving naloxegol (3%) at the higher dose (25 mg/day) than those 
receiving the 12.5 mg/day dose (1%). The HHS asserts that the 
withdrawal symptoms reported did not always meet the criteria of a 
clinically meaningful opioid withdrawal syndrome.

3. The State of Current Scientific Knowledge Regarding the Drug or 
Other Substance

    Naloxegol is known as (5[alpha],6[alpha])-17-allyl-6-((20-hydroxy-
3,6,9,12,15,18-hexaoxaicos-1-yl)oxy)-4,5-epoxymorphinon-3,14-diol and 
also as alpha-6mPEG7-O-naloxol. The CAS number is 854601-70-0. The 
molecular formula of naloxegol is C34H53NO11 and the molecular weight 
is 651.8 g/mol. It is a white to off-white powder and is soluble in 
aqueous solvents over a pH range of 1 to 7.5. Naloxegol is synthesized 
in a five-step process from naloxone hydrochloride, an opioid 
antagonist derived from thebaine. Naloxegol (25 mg/day) is rapidly 
absorbed following oral administration in healthy volunteers. Maximum 
plasma concentrations were reached in 1.5 to 2 hours. The plasma half-
life (t \1/2\) is 7 to 9 hours, with a maximal plasma concentration 
(Cmax) of 45 ng/ml. In a drug distribution study in humans with 
radiolabeled naloxegol, the highest levels of radioactivity were in the 
liver and kidneys. The elimination t \1/2\ of naloxegol is rapid, with 
majority being eliminated within 24-hours post-dose.

4. Its History and Current Pattern of Abuse

    According to HHS, there has been no evidence of abuse-related 
signals from the human clinical trials. Naloxegol is a mu opioid 
antagonist, which as a class does not have abuse potential.

5. The Scope, Duration, and Significance of Abuse

    There have been no reports of abuse of naloxegol. According to the 
National Forensic Laboratory Information System (NFLIS) \4\ and the 
System to Retrieve Information from Drug Evidence (STRIDE),\5\ there 
have been no reports of naloxegol seizures from 2010 to the present.
---------------------------------------------------------------------------

    \4\ The National Forensic Laboratory Information System (NFLIS) 
is a program of the DEA, Office of Diversion Control. NFLIS 
systematically collects drug identification results and associated 
information from drug cases submitted to and analyzed by State and 
local forensic laboratories. NFLIS represents an important resource 
in monitoring illicit drug abuse and trafficking, including the 
diversion of legally manufactured pharmaceuticals into illegal 
markets. NFLIS is a comprehensive information system that includes 
data from forensic laboratories that handle approximately 90% of an 
estimated 1.0 million distinct annual State and local drug analysis 
cases. NFLIS includes drug chemistry results from completed analyses 
only. While NFLIS data is not direct evidence of abuse, it can lead 
to an inference that a drug has been diverted and abused. See 76 FR 
77330, 77332, Dec. 12, 2011.
    \5\ The System to Retrieve Information from Drug Evidence 
(STRIDE) is a database of drug exhibits sent to DEA laboratories for 
analysis. Exhibits from the database are from the DEA, other federal 
agencies, and local law enforcement agencies.
---------------------------------------------------------------------------

6. What, if Any, Risk There Is to the Public Health

    According to the HHS, naloxegol is well-tolerated and safe at the 
therapeutic doses of 12.5 mg and 25 mg. Preclinical and clinical 
studies showed no evidence of potential for abuse of naloxegol and thus 
there is little public health risk from naloxegol.

[[Page 64352]]

7. Its Psychic or Physiological Dependence Liability

    There were no symptoms of physical dependence in a naloxegol 
physical dependence liability study in rats. The HHS also mentioned 
that the lack of naloxegol self-administration by animals is consistent 
with a lack of psychic dependence liability.

8. Whether the Substance is an Immediate Precursor of a Substance 
Already Controlled Under the CSA

    Naloxegol is not considered an immediate precursor of any 
controlled substance.

Conclusion

    Based on consideration of the scientific and medical evaluation and 
accompanying recommendation of the HHS, and based on the DEA's 
consideration of its own eight-factor analysis, the DEA finds that 
these facts and all relevant data demonstrate that naloxegol does not 
possess abuse or dependence potential. Accordingly, the DEA finds that 
naloxegol does not meet the requirements for inclusion in any schedule, 
and should be removed from control under the CSA.

Regulatory Analyses

Executive Orders 12866 and 15363

    In accordance with 21 U.S.C. 811(a), this scheduling action is 
subject to formal rulemaking procedures done ``on the record after 
opportunity for a hearing,'' which are conducted pursuant to the 
provisions of 5 U.S.C. 556 and 557. The CSA sets forth the criteria for 
scheduling a drug or other substance. Such actions are exempt from 
review by the Office of Management and Budget (OMB) pursuant to section 
3(d)(1) of Executive Order 12866 and the principles reaffirmed in 
Executive Order 13563.

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 
to eliminate drafting errors and ambiguity, minimize litigation, 
provide a clear legal standard for affected conduct, and promote 
simplification and burden reduction.

Executive Order 13132

    This rulemaking does not have federalism implications warranting 
the application of Executive Order 13132. The rule does not have 
substantial direct effects on the States, on the relationship between 
the Federal Government and the States, or the distribution of power and 
responsibilities among the various levels of government.

Executive Order 13175

    This rule does not have tribal implications warranting the 
application of Executive Order 13175. This rule does not have 
substantial direct effects on one or more Indian tribes, on the 
relationship between the Federal Government and Indian tribes, or on 
the distribution of power and responsibilities between the Federal 
Government and Indian tribes.

Regulatory Flexibility Act

    The Deputy Administrator, in accordance with the Regulatory 
Flexibility Act (5 U.S.C. 601-612) (RFA), has reviewed this proposed 
rule and by approving it certifies that it will not have a significant 
economic impact on a substantial number of small entities. The purpose 
of this rule is to remove naloxegol from the list of schedules of the 
CSA. This action will remove regulatory controls and administrative, 
civil, and criminal sanctions applicable to controlled substances for 
handlers and proposed handlers of naloxegol. Accordingly, it has the 
potential for some economic impact in the form of cost savings.
    Naloxegol is a new molecular entity and is not currently available 
or marketed in any country. According to publicly available information 
reviewed by the DEA, naloxegol is anticipated to enjoy patent 
protection for an extended period of time before generic equivalents 
may be manufactured and marketed in the United States. Although the 
number of manufacturers of naloxegol may initially be limited, there is 
potential for numerous handlers in various business activities, e.g., 
distributors, hospitals/clinics, pharmacies, practitioners, etc.
    If finalized, the proposed rule will affect all persons who would 
handle, or propose to handle, naloxegol. Due to the wide variety of 
unidentifiable and unquantifiable variables that potentially could 
influence the distribution and dispensing rates of new molecular 
entities, the DEA is unable to determine the number of entities and 
small entities which might handle naloxegol. However, the DEA estimates 
that all persons who would handle, or propose to handle naloxegol, are 
currently registered with the DEA to handle schedule II controlled 
substances. Therefore, the 1.5 million (1,469,418 as of September 2014) 
controlled substance registrations, representing approximately 426,714 
entities, would be the maximum number of entities affected by this 
rule. The DEA estimates that 417,302 (97.8%) of 426,714 affected 
entities are ``small entities'' in accordance with the RFA and Small 
Business Administration size standards.
    The DEA estimates all controlled substances registrants handle both 
controlled and non-controlled substances and these registrants are 
expected to continue to handle naloxegol if the proposed rule were 
finalized. Additionally, since prospective naloxegol handlers are 
likely to handle other schedule II controlled substances, the cost 
savings they would receive as a result of the de-control of naloxegol 
would be nominal. As naloxegol handlers continue to handle other 
scheduled II controlled substances, they will need to maintain their 
DEA registration and keep the same security and recordkeeping 
processes, equipment, and facilities in place and would experience only 
a nominal reduction in security, inventory, recordkeeping, and labeling 
costs.
    While the DEA does not have a basis to estimate the number of 
affected entities, the DEA estimates that the maximum number of 
affected entities is 426,714 of which 417,302 are estimated to be small 
entities. Since the affected entities are expected to handle other 
schedule II controlled substances and maintain security and 
recordkeeping facilities and processes consistent with schedule II 
controlled substances handling requirements, the DEA estimates any 
economic impact (cost savings) will be nominal. Because of these facts, 
this rule will not result in a significant economic impact on a 
substantial number of small entities.

Unfunded Mandates Reform Act of 1995

    On the basis of information contained in the ``Regulatory 
Flexibility Act'' section above, the DEA has determined and certifies 
pursuant to the Unfunded Mandates Reform Act of 1995 (UMRA), 2 U.S.C. 
1501 et seq., that this action would not result in 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 for inflation) in any one year * * *.'' 
Therefore, neither a Small Government Agency Plan nor any other action 
is required under provisions of UMRA.

Paperwork Reduction Act

    This action does not impose a new collection of information 
requirement under the Paperwork Reduction Act, 44 U.S.C. 3501-3521. 
This action would not impose recordkeeping or reporting requirements on 
State or local governments, individuals, businesses, or

[[Page 64353]]

organizations. An agency may not conduct or sponsor, and a person is 
not required to respond to, a collection of information unless it 
displays a currently valid OMB control number.

List of Subjects in 21 CFR Part 1308

    Administrative practice and procedure, Drug traffic control, 
Reporting and recordkeeping requirements.

    For the reasons set out above, 21 CFR part 1308 is proposed to be 
amended to read as follows:

PART 1308--SCHEDULES OF CONTROLLED SUBSTANCES

0
1. The authority citation for 21 CFR part 1308 continues to read as 
follows:

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

0
2. In Sec.  1308.12, amend the introductory text of paragraph (b)(1) by 
adding the word ``naloxegol,'' between ``nalmefene,'' and ``naloxone,'' 
to read as follows:


Sec.  1308.12  Schedule II.

    (a) * * *
    (b) * * *
    (1) Opium and opiate, and any salt, compound, derivative, or 
preparation of opium or opiate excluding apomorphine, thebaine-derived 
butorphanol, dextrorphan, nalbuphine, nalmefene, naloxegol, naloxone, 
and naltrexone, and their respective salts, but including the 
following:
* * * * *

    Dated: October 23, 2014.
Thomas M. Harrigan,
Deputy Administrator.
[FR Doc. 2014-25685 Filed 10-28-14; 8:45 am]
BILLING CODE 4410-09-P