[Federal Register Volume 84, Number 183 (Friday, September 20, 2019)]
[Notices]
[Pages 49530-49535]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-20372]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2019-N-3403]


The Food and Drug Administration Solicits Input on Potential Role 
for Abuse-Deterrent Formulations of Central Nervous System Stimulants; 
Establishment of a Public Docket; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; establishment of a public docket; request for comments.

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SUMMARY: The Food and Drug Administration (FDA) is establishing a 
public docket to receive comments from interested parties, including 
patients, patient advocates, healthcare providers, academics, 
researchers, the pharmaceutical industry, and other government 
entities, on considerations related to the development and evaluation 
of abuse-deterrent formulations (ADFs) of central nervous system 
stimulants and whether such products could play a role in addressing 
public health concerns related to prescription stimulant misuse and 
abuse. This notice provides an overview of available postmarket data on 
the use, misuse, and abuse of prescription stimulants and associated 
morbidity and mortality, along with similar data on prescription 
opioids to provide context; background information on the development 
and evaluation of ADF products; and specific questions on which FDA 
seeks input. The Appendix lists the sources used in developing this 
overview.

DATES: Submit either electronic or written comments by November 19, 
2019.

ADDRESSES: FDA is establishing a docket for public comment. The docket 
number is FDA-2019-N-3403. The docket will close on November 19, 2019. 
Please note that late, untimely filed comments will not be considered. 
Electronic comments must be submitted on or before November 19, 2019. 
The https://www.regulations.gov electronic filing system will accept 
comments until 11:59 p.m. Eastern Time at the end of November 19, 2019. 
Comments received by mail/hand delivery/courier (for written/paper 
submissions) will be considered timely if they are postmarked or the 
delivery service acceptance receipt is on or before that date.
    You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and

[[Page 49531]]

Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2019-N-3403 for ``FDA Solicits Input on Potential Role for Abuse-
Deterrent Formulations of Central Nervous System Stimulants; 
Establishment of a Public Docket; Request for Comments.'' Received 
comments, those filed in a timely manner (see ADDRESSES), will be 
placed in the docket and, except for those submitted as ``Confidential 
Submissions,'' publicly viewable at https://www.regulations.gov or at 
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through 
Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' FDA will review 
this copy, including the claimed confidential information, in its 
consideration of comments. The second copy, which will have the claimed 
confidential information redacted/blacked out, will be available for 
public viewing and posted on https://www.regulations.gov. Submit both 
copies to the Dockets Management Staff. If you do not wish your name 
and contact information be made publicly available, you can provide 
this information on the cover sheet and not in the body of your 
comments and you must identify the information as ``confidential.'' Any 
information marked as ``confidential'' will not be disclosed except in 
accordance with 21 CFR 10.20 and other applicable disclosure law. For 
more information about FDA's posting of comments to public dockets, see 
80 FR 56469, September 18, 2015, or access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Janelle Derbis, Center for Drug 
Evaluation and Research (HFD-1), Food and Drug Administration, 20 North 
Michigan Ave., Suite 510, Chicago, IL 60602, 312-596-6516.

SUPPLEMENTARY INFORMATION:

I. Introduction

    Prescription central nervous system (CNS) stimulants are important 
medications that are widely prescribed for the treatment of attention 
deficit hyperactivity disorder (ADHD) and, in some cases, narcolepsy. 
Currently marketed prescription stimulant drugs consist primarily of 
amphetamine salts and related compounds including methylphenidate, 
dextroamphetamine, dexmethylphenidate, methamphetamine, and 
lisdexamfetamine. When used properly, prescription stimulants can 
provide significant benefits for patients. However, these drugs have a 
high potential for misuse and abuse,\1\ with associated morbidity and 
mortality. As such, these drugs are classified in Schedule II (CII) 
under the Controlled Substances Act, the most restrictive 
classification for drugs with currently accepted medical use in the 
United States.
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    \1\ In this document, the term misuse refers to the intentional 
therapeutic use of a drug product in an inappropriate way and 
specifically excludes the definition of abuse. The term abuse is 
used here to mean the intentional, non-therapeutic use of a drug 
product or substance, even once, to achieve a desirable 
psychological or physiological effect.
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    Over the past several years, drug manufacturers have sought to 
develop novel formulations of prescription stimulants with properties 
intended to deter abuse. The purpose of this Federal Register notice is 
to solicit input on considerations related to the development and 
evaluation of such potentially abuse-deterrent formulations, referred 
to in this notice as ADF stimulants, and whether such products could 
play a role in addressing public health concerns related to 
prescription stimulant misuse and abuse. We note that although FDA has 
approved multiple opioid analgesic products with ADFs with labeling 
stating that these products are expected to deter abuse via one or more 
routes of administration, FDA has not approved similar labeling for any 
prescription stimulants. FDA recognizes the misuse and abuse of 
prescription stimulants as serious public health concerns. However, the 
scope and patterns of misuse and abuse, morbidity, and mortality 
associated with prescription stimulants are different from those 
associated with prescription opioids. Furthermore, postmarket data 
regarding the impact of ADF opioid analgesics in reducing abuse and 
associated adverse health outcomes, such as overdose, continue to be 
limited. FDA is interested in public comment on whether and to what 
extent ADF stimulants might reduce prescription stimulant abuse and on 
the potential public health impact of any such reduction.

II. Background

    To better understand the potential role for ADF stimulant products, 
FDA has reviewed available postmarket data on patterns of use, misuse, 
and abuse of prescription stimulants and associated morbidity and 
mortality. A summary of these findings is presented below. To provide 
context, we also include selected similar data on prescription opioids 
(see the Appendix for the sources used to develop this summary). 
Finally, we briefly describe certain key concepts associated with the 
development and evaluation of drug products intended to deter abuse.

A. Postmarket Data on Use, Misuse, Abuse, and Related Adverse Health 
Outcomes

    Amphetamine stimulants have been available and used for various 
medical purposes for roughly a century. In the 1990s, longer acting 
forms of amphetamine were introduced to the market. During this same 
period, a steep increase in the diagnosis of ADHD in the United States 
led to a parallel increase in societal exposure to prescribed 
amphetamine and related stimulant products. From 2007 to 2016, the 
number of individuals receiving prescriptions for stimulants increased 
substantially in patients older than 4 years old, with the greatest 
rate increases occurring in those aged 25 to 44 years. From 2012 to 
2016, the estimated number of prescriptions dispensed annually for CII 
stimulant products from U.S. outpatient retail pharmacies increased 
from approximately 49.2 million to 62.8 million prescriptions. During 
this same period, the estimated number of prescriptions dispensed for 
opioid analgesics decreased from approximately 238.2 million to 193.4 
million, remaining approximately three times that of CII stimulant 
product prescriptions dispensed in 2016.
    College students and other young adults are the demographic groups 
with the highest prevalence of misuse and abuse of prescription 
stimulants. Data

[[Page 49532]]

from the National Survey on Drug Use and Health (2017) suggest that 
among Americans aged 12 years and older, an estimated 6.8 percent have 
used a prescription stimulant in the past year, and 2.1 percent have 
misused or abused a prescription stimulant. Among those aged 18 to 25 
years, an estimated 14.7 percent have used a prescription stimulant in 
the past year, and 7.4 percent report misusing or abusing the 
medications. By comparison, among those 12 years and older, an 
estimated 33.4 percent used and 4.1 percent misused or abused 
prescription opioid analgesics in the past year. Among 18- to 25-year-
olds, an estimated 29.9 percent used prescription opioid analgesics in 
the past year, and 7.2 percent reported misusing or abusing the 
medications.
    Most individuals misusing or abusing prescription stimulants report 
doing so only occasionally, primarily to stay awake or enhance academic 
or work performance, rather than to achieve a high. Those who misuse 
and abuse prescription stimulants commonly do so in the setting of 
polysubstance abuse involving a wide range of other prescription 
products and illicit substances. Limited data from surveys of college 
students suggest that the problem of prescription stimulant misuse and 
abuse may be growing in this population, although the prevalence 
appears to vary considerably by geographic region. Recent data from 
U.S. poison control centers suggest that misuse and abuse of 
prescription stimulants may be declining among adolescents less than 19 
years of age.
    In surveys, a large majority of college students who misuse or 
abuse prescription stimulants report doing so by the oral route. 
However, a sizable minority report at least sometimes using them 
intranasally (most estimates being between 10 percent and 30 percent, 
but ranging from approximately 7 percent to 50 percent). Injection of 
prescription stimulants appears to be very uncommon among college 
students, although data are limited. Among individuals being assessed 
for or entering substance abuse treatment--a population enriched with 
individuals with advanced substance use disorders (SUDs)--about 2 in 5 
respondents reporting misuse or abuse of prescription stimulants 
indicate using them intranasally, and approximately 1 in 10 reports 
injecting them. Direct comparisons with routes of abuse for 
prescription opioids are difficult, because these patterns vary widely 
across class, but the routes of abuse patterns for prescription 
stimulants appear most similar to those seen in this population for 
immediate-release oxycodone/acetaminophen combination products.
    A variety of serious adverse events have been reported in 
association with prescription stimulant misuse and abuse, including 
both acute and chronic cardiovascular and neuropsychiatric effects. 
Additional serious complications are associated with abuse via non-oral 
routes, including but not limited to, pulmonary complications and 
infections from non-sterile injection practices and syringe sharing. 
Misuse and abuse of prescription stimulants can result in physical and 
psychological dependence as well as impairment of important family, 
social, and occupational functioning.
    Despite these concerns, available data from emergency department 
(ED) visits, drug-involved mortality, and treatment center admissions 
suggest that serious consequences of prescription stimulant misuse and 
abuse appear to be considerably less frequent than for prescription 
opioids, even after accounting for the lower prescription volume of 
stimulants. It is important to recognize that not all harms associated 
with prescription drug misuse and abuse will be captured in these data 
sources. Based on data from the National Electronic Injury Surveillance 
System-Cooperative Adverse Drug Event Surveillance (NEISS-CADES) 
project, in 2016, approximately 11,000 emergency department visits were 
estimated to involve nonmedical use of prescription stimulants 
(including both misuse and abuse), or approximately 1 visit for every 
5,700 prescriptions dispensed. In the same year, approximately 130,000 
visits were estimated to involve nonmedical use of opioid analgesics, 
or 1 visit for every 1,500 prescriptions dispensed. Therefore, although 
survey data indicate that the prevalence of prescription stimulant 
misuse and abuse is similar to, or potentially even higher than, that 
of opioid analgesics relative to prescribed availability, the ED visit 
data suggest that the likelihood of acute adverse effects serious 
enough to require medical evaluation or treatment is considerably lower 
with prescription stimulants than with opioid analgesics. This finding 
is not surprising given the risk of profound central nervous system and 
respiratory depression associated with opioids.
    Similarly, deaths involving prescription opioids vastly outnumber 
those involving prescription stimulants, despite the only modestly 
higher prescription volume for opioids. Based on data extracted from 
the text of U.S. death certificates, in 2014, approximately 1,000 
deaths involved prescription stimulants (including mention of 
``amphetamines'' and other prescription stimulants but excluding 
``methamphetamine''), or 1 death for every 55,000 prescriptions. By 
comparison, in 2014, more than 14,000 deaths involved prescription 
opioids, about 1 death for every 16,000 prescriptions dispensed.
    Data from SUD treatment center admissions indicate that 
prescription stimulants are a relatively uncommon drug of abuse 
reported among those entering treatment for SUDs (<2 percent), 
particularly when compared to prescription opioids (approximately 8 to 
20 percent). However, as these data capture only a snapshot of recent 
drug use reported by people being assessed for treatment, they shed 
little light on the natural history of drug abuse and the development 
of SUDs, which often involve multiple drugs. Although there is a small 
body of literature on the progression of opioid use disorder and 
transitions from prescription opioids to heroin, there has been little 
research on the longitudinal trajectory of prescription stimulant 
misuse and abuse, the development of addiction among those misusing or 
abusing these drugs, or the likelihood of transitioning to illicit 
stimulants, such as methamphetamine and cocaine, which represent a 
large and growing public health concern.
    In summary, prescription stimulant misuse and abuse are serious 
public health concerns, particularly in college students and other 
young adults. Most misuse and abuse of these drugs is oral, although a 
significant minority of those misusing and abusing the medications 
report non-oral routes, primarily intranasal. The risk of serious 
adverse outcomes and the overall magnitude of harms associated with 
prescription stimulants appear to be considerably lower than for 
prescription opioids. The relationship between misuse and abuse of 
prescription stimulants and the development of addiction or initiation 
of illicit stimulants, such as methamphetamine and cocaine, or other 
substances, has not been well characterized.

B. Development and Evaluation of ADF Products

    Some examples of types of abuse-deterrent technologies and methods 
for evaluating ADFs are outlined in FDA's 2015 guidance for industry 
entitled ``Abuse-Deterrent Opioids--Evaluation and Labeling'' 
(available at https://www.fda.gov/media/84819/download). While this 
document was not intended to provide guidance on the development or 
evaluation of abuse-deterrent

[[Page 49533]]

products in other drug classes, it outlines certain principles that 
would likely be relevant to the development and evaluation of abuse-
deterrent formulations of any prescription drug product. For example, 
the guidance explains that the design of relevant abuse-deterrent 
products should target specific known or expected routes of abuse 
relevant to the proposed product. In addition, the guidance recommends 
that an evaluation of a proposed ADF should take into consideration the 
known routes of abuse for the non-ADF predecessor or similar products, 
and that an ADF should meaningfully reduce abuse of the product as well 
as morbidity and mortality associated with that abuse. The potential 
for an ADF to reduce abuse and misuse of a drug product and associated 
harms depends on, among other things, the pharmacologic properties and 
abuse liability of the drug substance itself, the scope and patterns of 
abuse and related harms for that drug and other drugs in the community, 
and the effectiveness of the ADF in actually deterring abuse and 
reducing related adverse outcomes associated with that drug in real-
world settings. The guidance recommends that developers of ADF products 
should also consider possible unintended consequences of the ADF, such 
as the possibility that the ADF could result in shifting abuse from one 
route to a different, riskier route (e.g., from snorting to injecting).
    Although certain scientific principles described in the 2015 
guidance likely would be relevant to the development and evaluation of 
abuse-deterrent formulations of any prescription drug product, FDA has 
not determined that ADF stimulants warrant the same regulatory approach 
as ADF opioids. FDA has approved several ADF opioids with language in 
product labeling stating that these products are expected to deter 
abuse via specific routes of administration, but has not approved 
similar labeling for any prescription stimulants. As discussed above, 
both the patterns and magnitudes of misuse and abuse, morbidity, and 
mortality associated with prescription stimulants are quite different 
from those associated with prescription opioids. Furthermore, FDA is 
continuing to refine its regulatory approach towards ADF opioids in 
light of evolving technology and science as well as the changing nature 
of the opioid crisis. While some stakeholders have called for FDA to 
take additional actions to encourage the transition of the prescription 
opioid market to ADF opioids, others have questioned the effectiveness 
of ADFs in reducing opioid abuse and have raised concerns about the 
possibility of unintended consequences of such a transition, including 
higher costs and the potential to shift abuse to even more dangerous 
illicit drugs.

C. Topics for Consideration

    (1) FDA has provided a summary of its current understanding of 
abuse and misuse of prescription stimulant products in the United 
States. We are seeking new or additional information and perspectives 
on prescription stimulant misuse and abuse and associated harms. We are 
particularly interested in data on the natural history of stimulant use 
disorders, including the risk of developing addiction and of 
transitioning to abuse of illicit stimulants.
    (2) Taking into account the patterns and consequences of 
prescription stimulant misuse and abuse by both patients and others who 
may access the drugs, discuss whether ADF stimulants could be expected 
to meaningfully reduce prescription stimulant abuse and associated 
harms. For which specific patient populations, if any, might it be 
beneficial to prescribe ADF stimulants? In particular, please discuss 
whether and to what extent ADF stimulants might be expected to deter 
the various routes of abuse (e.g., oral, intranasal, injection) 
associated with prescription stimulants, and also whether such 
products, if approved and marketed, could be expected to meaningfully 
reduce the incidence or progression of stimulant use disorder.
    (3) Please comment on how ADF stimulant products should be 
evaluated in premarket and postmarket studies to determine whether they 
can be expected to deter, or actually have deterred, abuse by the 
various routes associated with prescription stimulant abuse (oral, 
intranasal, intravenous, inhalation).
    (4) Comment on whether the potentially abuse-deterrent properties 
of ADF stimulants should be described in product labeling. If so, how 
should they be described and based on what evidence? We additionally 
invite comment on whether terms such as abuse deterrent stimulant and 
ADF stimulant could be misinterpreted by the public (including 
prescribers) to suggest that a product is ``abuse-proof,'' or carries a 
lower risk of addiction. Is there alternative terminology that FDA 
could use to more clearly describe the expected effects of these new 
formulations in terms of patient safety and public health?
    (5) What other actions or regulatory approaches with respect to ADF 
stimulants should FDA consider?
    (6) Comment on any potential unintended consequences of introducing 
ADF stimulants to the market. For example, what is the potential for 
ADF stimulants to shift behavior toward more dangerous routes of abuse 
(i.e., injection) or to more dangerous drugs (e.g., illicit 
methamphetamine or other substances), or to result in increased costs 
for patients, payers, or health systems?
    (7) What other actions, if any, should FDA consider to reduce 
misuse, abuse, and related harms associated with prescription 
stimulants?

III. Appendix

    The following sources were used in developing the body of this 
notice.

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[[Page 49534]]

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of Pontine Hemorrhage Related to Methamphetamine Abuse.'' Journal of 
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Granulomatosis Caused by Intravenous Administration of 
Methylphenidate.'' Nihon Kokyuki Gakkai Zasshi, 36(1): 111-115.
Pereiro-G[oacute]mez, C., J. Vicente-Alba, A. Ramos-Caneda, et al. 
(2012) ``Ekbom Syndrome in an Intravenous Methylphenidate Abuser.'' 
Adicciones, 24(4): 301-307.
Rabiner, D.L., A.D. Anastopoulos, E.J. Costello, et al. (2009) ``The 
Misuse and Diversion of Prescribed ADHD Medications by College 
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    Dated: September 16, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-20372 Filed 9-19-19; 8:45 am]
 BILLING CODE 4164-01-P


