Proposed Aggregate Production Quotas for Schedule I and II Controlled Substances and Assessment of Annual Needs for the List I Chemicals Ephedrine, Pseudoephedrine, and Phenylpropanolamine for 2025

SUPPLEMENTARY INFORMATION:

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Legal Authority

Section 306 of the Controlled Substances Act (21 U.S.C. 826) requires the Attorney General to establish production quotas for each basic class of controlled substances listed in schedules I and II, and for the list I chemicals ephedrine, pseudoephedrine, and phenylpropanolamine. The Attorney General has delegated this function to the Administrator of DEA pursuant to 28 CFR 0.100.

Analysis for Proposed 2025 Aggregate Production Quotas and Assessment of Annual Needs

The proposed 2025 aggregate production quotas (APQ) and assessment of annual needs (AAN) represent those quantities of schedule I and II controlled substances, and the list I chemicals ephedrine, pseudoephedrine, and phenylpropanolamine, to be manufactured in the United States in 2025 to provide for the estimated medical, scientific, research, and industrial needs of the United States, lawful export requirements, and the establishment and maintenance of reserve stocks. These quotas include imports of ephedrine, pseudoephedrine, and phenylpropanolamine, but do not include imports of controlled substances for use in industrial processes.

Aggregate Production Quotas

In determining the proposed 2025 APQ, the Administrator has taken into account the criteria of 21 U.S.C. 826(a) and 21 CFR 1303.11, including the following seven factors:

(1) Total net disposal of the class by all manufacturers during the current and two preceding years;

(2) Trends in the national rate of net disposal of the class;

(3) Total actual (or estimated) inventories of the class and of all substances manufactured from the class, and trends in inventory accumulation;

(4) Projected demand for such class as indicated by procurement quotas requested pursuant to [21 CFR] 1303.12;

(5) The extent of any diversion of the controlled substance in the class;

(6) Relevant information obtained from the Department of Health and Human Services (HHS), including from the Food and Drug Administration (FDA), the Centers for Disease Control and Prevention (CDC), and the Centers for Medicare and Medicaid Services (CMS), and relevant information obtained from the states; and

(7) Other factors affecting medical, scientific, research, and industrial needs in the United States and lawful export requirements, as the Administrator finds relevant, including changes in the currently accepted medical use in treatment with the class or the substances manufactured from it, the economic and physical availability of raw materials for use in manufacturing and for inventory purposes, yield and stability problems, potential disruptions to production (including possible labor strikes), and recent unforeseen emergencies such as floods and fires.

21 CFR 1303.11(b).

DEA formally solicited input from FDA and CDC in February of 2024 and from the states in April 2024, as required by 21 U.S.C. 826 and 21 CFR part 1303. DEA did not solicit input from CMS for reasons discussed in previous notices. DEA requested information on trends in the legitimate use of select schedule I and II controlled substances from FDA and rates of overdose deaths for covered controlled substances from CDC. DEA's request for information from the states was made directly to the Prescription Drug Monitoring Program (PDMP) Administrators in each state as well as through the National Association of State Controlled Substances Authorities (NASCSA).

Assessment of Annual Needs

In similar fashion, in determining the proposed 2025 AAN for the list I chemicals ephedrine, pseudoephedrine, and phenylpropanolamine, the Administrator has taken into account the criteria of 21 U.S.C. 826(a) and 21 CFR 1315.11, including the following five factors:

(1) Total net disposal of the chemical by all manufacturers and importers during the current and two preceding years;

(2) Trends in the national rate of net disposal of each chemical;

(3) Total actual (or estimated) inventories of the chemical and of all substances manufactured from the chemical, and trends in inventory accumulation;

(4) Projected demand for each chemical as indicated by procurement and import quotas requested pursuant to [21 CFR] 1315.32; and

(5) Other factors affecting medical, scientific, research, and industrial needs in the United States, lawful export requirements, and the establishment and maintenance of reserve stocks, as the Administrator finds relevant, including changes in the currently accepted medical use in treatment with the chemicals or the substances manufactured from them, the economic and physical availability of raw materials for use in manufacturing and for inventory purposes, yield and stability problems, potential disruptions to production (including possible labor strikes), and recent unforeseen emergencies such as floods and fires.

21 CFR 1315.11(b).

In determining the proposed 2025 AAN, DEA used the calculation methodology previously described in the 2010 and 2011 assessments of annual needs (74 FR 60294 (Nov. 20, 2009) and 75 FR 79407 (Dec. 20, 2010), respectively).

Estimates of Medical Need for Schedule II Opioids and Stimulants

In accordance with 21 CFR part 1303, 21 U.S.C. 826, and 42 U.S.C. 242, HHS continues to provide DEA with estimates of the quantities of select schedule I and II controlled substances and three list I chemicals that will be required to meet the legitimate medical needs of the United States for a given calendar year. The responsibility to provide these estimates of legitimate domestic medical needs resides with FDA. FDA provides DEA with predicted estimates of domestic medical usage for selected controlled substances based on information available to them at a specific point in time in order to meet statutory requirements.

FDA predicts that levels of medical need for schedule II opioids in the United States in calendar year 2025 will decline on average 6.6 percent from calendar year 2024 levels. These declines are expected to occur across a variety of schedule II opioids including fentanyl, hydrocodone, hydromorphone, oxycodone, and oxymorphone. DEA considered the potential for diversion of schedule II opioids, as required by 21 CFR 1303.11(b)(5), as well as a potential increase in demand for certain opioids identified as being necessary to support the previously postponed elective surgeries now that the COVID-19 public health emergency (PHE) has ended, pursuant to 21 CFR 1303.11(b)(7), in developing the proposed 2025 APQ.

FDA predicted an average of a 3.5 percent increase in domestic medical use of the schedule II stimulants amphetamine, methylphenidate (including dexmethylphenidate), and lisdexamfetamine, which are prescribed to treat patients with attention deficit hyperactivity disorder (ADHD) and more recently prescribed off-label to treat patients diagnosed with long-COVID symptoms commonly known as brain fog where fatigue and cognitive impairment persist 4 to 12 weeks after a COVID infection. FDA also raised concerns over drug shortage notifications it received since 2022 from patients for specific ADHD medications containing amphetamine, lisdexamfetamine, and methylphenidate. FDA's stated reasons for these specific shortages include increased prescribing potentially related to the growth in telemedicine during and after the COVID-19 PHE, supply chain issues, manufacturing and quality issues, lack of active ingredients, and business decisions of manufacturers. DEA considered FDA's concerns when determining the APQ for these substances. Additionally, DEA considered manufacturer and distributor-reported data which shows inventories for both amphetamine and methylphenidate-based products have increased year-over-year throughout the supply chain. DEA believes these increases in inventories combined with the established APQs are adequate to address FDA's estimated increases in domestic medical use for amphetamine and methylphenidate. With respect to lisdexamfetamine, DEA recently increased the APQ pursuant to a final order published on September 5, 2024 to address reported shortages. In sum, DEA believes that manufacturers will be able to meet the increase in domestic medical need for these three schedule II stimulants with the APQs proposed in this notice.

DEA Projected Trends for Certain Schedule I Controlled Substances

DEA is proposing a higher APQ for ibogaine than DEA granted for 2024 to support manufacturing activities related to the increased level of research and clinical trials with this schedule I controlled substance. Additionally, DEA proposes a higher APQ for gamma hydroxybutyric acid (GHB) to allow for an anticipated increase in domestic bulk manufacturing to meet forecasted and continued domestic market need due to the closure of a foreign manufacturing facility. Imports of the schedule III oxybate form of GHB from that manufacturing facility have supplied an estimated 78% of the domestic need. Their foreign plant closure will be approximately one year in duration. GHB (oxybate) products are used in the treatment of patients diagnosed with narcolepsy and cataplexy.

Information Received for Consideration of the Remaining Factors

For the factors listed in 21 CFR 1303.11(b)(3) and (4), DEA registered manufacturers of controlled substances in schedules I and II provide information such as inventory, distribution, manufacturing, sales forecasts and quota requests to DEA database systems. See21 CFR 1303.12, 1303.22, and part 1304.

The regulation at 21 CFR 1303.11(b)(5) requires DEA to consider the extent of diversion of controlled substances. Diversion is defined as all distribution, dispensing, or other use of controlled substances for other than legitimate medical purposes. In order to consider the extent of diversion, DEA analyzed reports of diversion of controlled substances from 2023 submitted to its Theft Loss Report database. This database is comprised of DEA registrant reports documenting diversion from the legitimate distribution chain, including employee thefts, break-ins, armed robberies, and material lost in transit. The data was categorized by basic drug class, and the amount of active pharmaceutical ingredient (API) in the dosage form was delineated with an appropriate metric for use in proposing aggregate production quota values ( i.e., weight).

In this proposed 2025 APQ notice, DEA continues to consider the lingering effects of the COVID-19 pandemic on the global supply chain, pursuant to 21 CFR 1303.11(b)(7), and specifically the continued impacts on the availability of raw materials for use in the domestic manufacturing process. Additionally, DEA considered the impact of the demand for surgical care for elective surgeries that were deferred during the COVID-19 PHE.

Estimates of Diversion of Covered Controlled Substances

In establishing any quota . . . , or any procurement quota established by [DEA] by regulation, for fentanyl, oxycodone, hydrocodone, oxymorphone, or hydromorphone (in this subsection referred to as a “covered controlled substance”), [DEA] shall estimate the amount of diversion of the covered controlled substance that occurs in the United States. 21 U.S.C. 826(i)(1)(A).

In estimating diversion under that provision, DEA:

(i) shall consider information . . . , in consultation with the Secretary of Health and Human Services, [it] determines reliable on rates of overdose deaths and abuse and overall public health impact related to the covered controlled substance in the United States; and

(ii) may take into consideration whatever other sources of information [it] determines reliable.

21 U.S.C. 826(i)(1)(B).

The statute further mandates that DEA “make appropriate quota reductions, as determined by [DEA], from the quota [it] would have otherwise established had such diversion not been considered.”

In estimating the amount of diversion of each covered controlled substance that occurs in the United States, DEA considered information from state PDMP Administrators and from legitimate distribution chain participants.

Consideration of Information From Certain State PDMPs and From National Sales Data

Pursuant to 21 CFR 1303.11(b)(6), DEA requested state PDMP data for the purpose of establishing its APQ. DEA believes state PDMPs to be an essential, reliable source of information for use in effectively estimating diversion of the five covered controlled substances. In April 2024, DEA sent a letter to NASCSA requesting its assistance in obtaining aggregated PDMP data for the five covered controlled substances from each state covering the years 2021-2023. The letter indicated that DEA was specifically interested in an analysis of prescription data from each state's PDMP that would assist DEA in estimating diversion and setting appropriate quotas in compliance with 21 U.S.C. 826(i). In its request, DEA provided specific questions, discussed in detail below, based on common indicia of potential diversion known as “red flags” by physicians, pharmacists, manufacturers, distributors, and federal and state regulatory and law enforcement agencies. DEA investigators and administrative prosecutors also rely on Agency case law in which these red flags of diversion have been upheld as indicia of potential diversion. Certain state regulations now include red flag circumstances as potential indicators of illegitimate prescriptions, and thus of potential abuse and diversion of controlled substances. See, e.g., The Pharmacy Place Order, 86 FR 21008, 21012 (Apr. 21, 2021) (citing 22 Tex. Admin. Code 291.29(c)(4), specifying the geographical distance between the practitioner and the patient or between the pharmacy and the patient as a red flag).

DEA requested responses from state PDMP Administrators by June 15, 2024. NASCSA disseminated DEA's request to its PDMP Administrators and provided them with a report tool to ensure that responses to DEA's questions were extracted consistently across all responsive states. Twenty-nine states and three territories provided DEA with summarized PDMP data as of July 2024, utilizing the standardized report developed by NASCSA. See Table 1a below.