Federal Register / Vol. 87, No. 77 / Thursday, April 21, 2022 / Notices 23869 

1We use the term ‘‘nonmedical’’ in this document 

to refer to misuse of a drug, abuse of a drug, or both. 

‘‘Misuse’’ is the intentional use, for therapeutic 

purposes, of a drug in a manner other than 

prescribed. ‘‘Abuse’’ is the intentional, nontherapeutic use of a drug, even once, for its 

desirable psychological or physiological effects. 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2022–N–0165] 

Providing Mail-Back Envelopes and 

Education on Safe Disposal With 

Opioid Analgesics Dispensed in an 

Outpatient Setting; Establishment of a 

Public Docket; Request for Comments 

AGENCY: Food and Drug Administration, 

Health and Human Services (HHS). 

ACTION: Notice; establishment of a 

public docket; request for comments. 

SUMMARY: The Food and Drug 

Administration (FDA, the Agency, or 

we) is announcing the establishment of 

a docket to solicit public comment on a 

potential modification to the Opioid 

Analgesic Risk Evaluation and 

Mitigation Strategy (OA REMS) to 

require that mail-back envelopes be 

dispensed and education on safe 

disposal provided with opioid 

analgesics dispensed in an outpatient 

setting. Such a requirement could 

reduce the amount of unused opioid 

analgesics in patients’ homes, thereby 

reducing opportunities for nonmedical 

use, accidental exposure, and overdose, 

and possibly reducing the development 

of new opioid addiction. 

DATES: Submit either electronic or 

written comments by June 21, 2022. 

ADDRESSES: FDA is establishing a docket 

for public comment on this notice. The 

docket number is FDA–2022–N–0165. 

The docket will close on June 21, 2022. 

Submit either electronic or written 

comments by June 21, 2022. Please note 

that late, untimely filed comments will 

not be considered. Electronic comments 

must be submitted on or before June 21, 

2022. The https://www.regulations.gov 

electronic filing system will accept 

comments until 11:59 p.m. Eastern Time 

at the end of June 21, 2022. 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 

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– 

2022–N–0165 for ‘‘Providing Mail-Back 

Envelopes and Education on Safe 

Disposal With Opioid Analgesics 

Dispensed in an Outpatient Setting; 

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, 240–402–7500. 

• 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.’’ The 

Agency 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 to 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 this 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.govinfo.gov/content/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: 

Patrick Raulerson, Center for Drug 

Evaluation and Research, Food and 

Drug Administration, 10903 New 

Hampshire Ave., Bldg. 51, Rm. 6260, 

Silver Spring, MD 20993, 301–796– 

3522, Patrick.Raulerson@fda.hhs.gov. 

SUPPLEMENTARY INFORMATION: 

I. Background 

Nonmedical use,1 accidental 

exposure, and overdose associated with 

prescription opioid analgesics remain a 

serious problem in the United States. In 

2019, prescription pain relievers, such 

as opioid analgesics, remained the most 

common class of prescription drugs 

used nonmedically in the United States, 

with approximately 9.7 million people 

aged 12 and older reporting past-year 

nonmedical use (Ref. 1). Many people 

who use opioids nonmedically start 

with prescription opioid analgesics and 

transition to illicit substances (Refs. 2 to 

5). Also, from 2010 to 2018 there were 

over 48,000 accidental prescription 

opioid exposures in young children 

(Ref. 6). 

While the volume of prescription 

opioid analgesics dispensed has been 


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23870 Federal Register / Vol. 87, No. 77 / Thursday, April 21, 2022 / Notices 

2The percent of patients who dispose of unused 

medications. This document specifically discusses 

disposal of opioid analgesic medications. 

trending downward following a peak in 

2012, there were still an estimated 140.6 

million prescriptions, resulting in an 

estimated 8.7 billion units (e.g., tablets 

or capsules) dispensed in 2021 from 

U.S. outpatient retail and mail order 

pharmacies (Ref. 7). As of 2020, despite 

the decrease in opioid dispensing, 

prescription opioids were involved in 

more than 16,000 fatal overdoses per 

year (Ref. 8), higher than the number 

seen at the peak of opioid analgesic 

dispensing in 2012 (Ref. 9). The 

lethality of co-involved substances, such 

as heroin, illicitly manufactured 

fentanyl, and illicitly manufactured 

fentanyl analogues has also changed 

since 2012 and may partly explain why 

overdose deaths involving opioid 

analgesics persist, despite the 

reductions in prescribing. 

Patients commonly report having 

unused opioid analgesics after treatment 

of acute pain, such as pain following 

surgical procedures (Refs. 10 and 11). 

Opioid analgesics prescribed to treat 

chronic pain conditions can also result 

in unused drugs. When not properly 

disposed, these opioid analgesics 

provide opportunities for nonmedical 

use, accidental exposure, and overdose. 

Most people who reported past-year 

nonmedical use of prescription pain 

relievers obtained them through friends, 

relatives, or their own prescription (Ref. 

1). Accordingly, FDA’s efforts to address 

the opioid crisis include a focus on 

encouraging appropriate disposal of 

unused opioid analgesics. 

The Substance Use-Disorder 

Prevention that Promotes Opioid 

Recovery and Treatment for Patients 

and Communities Act (SUPPORT Act) 

(Pub. L. 115–271), signed into law on 

October 24, 2018, provides FDA several 

new authorities to address the opioid 

crisis. The SUPPORT Act authorized 

FDA to require through a Risk 

Evaluation and Mitigation Strategy 

(REMS) that a safe disposal packaging or 

safe disposal system for the purposes of 

rendering the drug nonretrievable be 

dispensed to certain patients with 

opioids or other drugs that pose a 

serious risk of abuse or overdose if, 

among other things, FDA determines 

that such safe disposal packaging or 

system may mitigate such risks and is 

sufficiently available (21 U.S.C. 355– 

1(e)(4)). 

The purpose of this notice is to seek 

public comment on the potential 

application of this authority to require, 

under the Opioid Analgesic (OA) REMS, 

that mail-back envelopes and education 

on safe disposal be provided with 

opioid analgesics dispensed in 

outpatient settings. We recognize that 

this is just one possible application of 

FDA’s new authorities in the Federal 

Food, Drug, and Cosmetic Act (FD&C 

Act) section 505–1(e)(4) (21 U.S.C. 355– 

1(e)(4)) related to packaging and 

disposal. We are considering, and invite 

comment on, other possible applications 

of these authorities, including novel 

packaging or other safe disposal options 

that would meet the SUPPORT Act 

standards. Furthermore, we actively 

encourage drug manufacturers and 

others to innovate in this space. We 

believe that the potential disposal 

requirement outlined below would 

provide patients and caregivers with a 

convenient additional option that would 

complement existing disposal options 

(e.g., take-back days, kiosks, flushing, 

and in-home disposal products). This 

potential requirement could be a 

significant and readily achievable step 

toward improving the safe use of opioid 

analgesics. 

FDA is establishing this docket to 

solicit input from stakeholders on all 

aspects of this potential requirement 

under the OA REMS, including 

comments on specific questions posed 

in section III of this notice. 

II. Mail-Back Envelopes Dispensed 

With Opioid Analgesics in an 

Outpatient Setting 

In this section, we identify available 

data showing that many patients do not 

use all of their prescribed opioid 

analgesics. This well-documented 

outcome results in unused opioid 

analgesics that, if not securely stored, 

may be easily accessible and subject to 

nonmedical use, accidental exposure, 

and overdose. We summarize published 

literature regarding the potential 

impacts of in-home disposal options 

and whether they could increase 

disposal of unused opioid analgesics, 

especially when coupled with patient 

education on the importance of 

disposal. We then describe existing 

disposal options and programs, 

including take-back days, collection 

kiosks in pharmacies and other 

locations, flushing, in-home disposal, 

and mail-back envelopes. We also 

describe a potential requirement, as part 

of the OA REMS, that mail-back 

envelopes and education on safe 

disposal be provided with opioid 

analgesics dispensed in an outpatient 

setting. 

A. Unused, Improperly Stored Opioids 

Provide an Easily Accessible Supply of 

Opioids for Nonmedical Use, Accidental 

Exposure, and Overdose 

Many patients report having excess 

opioid analgesic tablets from 

prescriptions they received after 

surgical procedures. A systematic 

review from 2017 reported that after 

seven common surgical procedures, 67 

to 92 percent of patients had excess 

opioid analgesics (Ref. 11). A more 

recent systematic review that included 

articles published up to 2019 

determined that, in studies of patientreported use of opioid analgesics after 

surgical procedures that reported on 

unused tablets, most studies reported 

that 50 to 70 percent of tablets went 

unused (Ref. 10). Articles published 

since the last systematic review 

continue to report excess tablets after 

treatment of acute pain from surgical 

procedures or from treatment in 

emergency departments (Refs. 12 to 21). 

Patients who are prescribed opioid 

analgesics to treat chronic pain may also 

have unused opioids requiring disposal, 

for example, when changing opioid 

therapy (new opioid ingredient or tablet 

strength), upon discontinuation of 

opioid therapy, or upon death. 

Removing unused opioids from a home 

is an important public health 

intervention as many studies report that 

patients frequently store opioid 

analgesic tablets in unsecure locations 

(Ref. 10), making them easily accessible 

for nonmedical use, accidental 

exposure, and overdose. 

B. Provision of Education and In-Home 

Disposal Options May Increase Disposal 

of Unused Opioid Analgesics 

Educating patients about opioid 

analgesic disposal options may increase 

the disposal rate 2 for unused opioids 

(Ref. 20). In a recent review of the 

literature examining opioid disposal 

options and practices, most studies 

found that fewer than 50 percent of 

patients disposed of their opioids (Ref. 

20). The majority of studies that 

examined the effect of providing patient 

education on the rate of disposing of 

unused postoperative opioids found that 

patient education increased the disposal 

rate by 15 to 30 percent compared to 

patients who did not receive any 

additional education. Two 

investigations found that text message 

reminders also increased the disposal 

rate by approximately 30 percent in the 

text message reminder group compared 

to patients who did not receive 

reminders (Refs. 21 and 22). 

There is also limited evidence that 

providing a disposal option along with 

education increased the probability of 

disposal over that of providing 

education alone. For example, one study 

assessed the difference in postoperative 

disposal rates when patients were 


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Federal Register / Vol. 87, No. 77 / Thursday, April 21, 2022 / Notices 23871 

3 79 FR 53520 at 53541, September 9, 2014. 

4Manufacturers, distributors, reverse distributors, 

narcotic treatment programs, hospitals/clinics with 

an onsite pharmacy, and retail pharmacies that 

desire to be collectors shall modify their registration 

to obtain authorization to be a collector (21 CFR 

1317.40(a); 1301.51). A collector would need to 

submit a letter of request for modification of their 

registration to the Registration Unit at the DEA and 

include the registrant’s name, address, registration 

number, and the type of collection (e.g., a mail-back 

program and/or a collection receptacle) that the 

collector intends to conduct. 

5 DEA regulations address take-back events, mailback programs, and collection receptacles (21 CFR 

1317.65, 1317.70, and 1317.75, respectively). 

6 21 CFR 1317.90(a). 

provided a take-home disposal method, 

patient education, or both (Ref. 23). 

Compared to usual care, either patient 

education or providing a take-home 

disposal method increased the disposal 

rate approximately 12 percent; for the 

group of patients who received both 

education and a take-home disposal 

method, the disposal rate increased by 

19.5 percent. The four studies where a 

disposal kit was provided uniformly 

reported an increase in actual or 

planned disposal rates, and in three of 

four studies, the rates increased to over 

50 percent of the study population 

(Refs. 23 to 26). 

While disposal products provided to 

patients in these studies were often not 

specified, and the study populations 

usually received them after hospital 

encounters for surgical procedures, it is 

reasonable to assume that similar 

increases in disposal rates may also 

occur with mail-back envelopes and for 

other situations outside of post-surgical 

pain. What is less clear is whether 

education provided in a retail pharmacy 

setting will be as successful as the 

patient education provided in a postsurgical setting. We are interested in 

descriptions of programs that provide 

mail-back envelopes specifically, as 

well as those in which patient 

counseling on disposal is provided at 

retail pharmacies. In addition to 

program descriptions, we are interested 

in data on the effectiveness of mail-back 

envelope provision and counseling on 

disposal provided at retail pharmacies 

in increasing opioid analgesic disposal 

rates. 

C. New REMS Authority Over Drug 

Disposal and Packaging 

Section 3032 of the SUPPORT Act 

amended FDA’s REMS authority. 

Specifically, as a part of a REMS, FDA 

may require that a drug for which there 

is a serious risk of an adverse event 

occurring from abuse or overdose be 

dispensed to certain patients with safe 

disposal packaging or a safe disposal 

system for purposes of rendering the 

drug ‘‘nonretrievable’’ (as that term is 

defined in a regulation adopted by the 

Drug Enforcement Administration 

(DEA)), if FDA determines that such safe 

disposal packaging or system may 

mitigate such serious risk and is 

sufficiently available (see section 505– 

1(e)(4) of the FD&C Act). Under DEA 

regulations (21 CFR 1317.90(a)), the 

requirement to render controlled 

substances ‘‘non-retrievable’’ applies 

only to DEA registrants and does not 

apply to ultimate users or patients.3

However, in the SUPPORT Act, 

Congress made the ‘‘nonretrievable’’ 

standard applicable to any safe disposal 

packaging or system FDA may require 

under a REMS (see 21 U.S.C. 355– 

1(e)(4)). FDA may also require that a 

drug for which there is such serious risk 

be made available for dispensing to 

certain patients in unit-dose packaging, 

packaging that provides a set duration, 

or another packaging system that FDA 

determines may mitigate that risk (21 

U.S.C. 355–1(e)(4)). 

A packaging or disposal requirement 

under this provision can be imposed for 

prescription drugs that are the subject of 

applications approved under section 

505(c) of the FD&C Act (21 U.S.C. 

355(c)) or section 351 of the Public 

Health Service Act, as well as drugs that 

are the subject of abbreviated new drug 

applications (ANDAs) approved under 

section 505(j) of the FD&C Act if a 

packaging or disposal requirement is 

required for the applicable reference 

listed drug (see section 505–1(i)(1)(B) of 

the FD&C Act). FDA can permit 

packaging systems and safe disposal 

packaging or safe disposal systems for 

drugs that are the subject of ANDAs that 

are different from those required for the 

applicable reference listed drugs (see 

section 505–1(i)(2)(B) of the FD&C Act). 

FDA must take into consideration the 

burden on patients’ access to the drug 

and the burden on the healthcare 

delivery system that would be 

associated with any such packaging or 

disposal requirement, and must consult 

with other relevant Federal Agencies 

with authorities over drug disposal 

packaging in certain circumstances (see 

section 505–1(e)(4) of the FD&C Act). 

The DEA has defined ‘‘nonretrievable’’ through regulation (21 CFR 

1300.05(b)). It means, in part, ‘‘the 

condition or state to which a controlled 

substance shall be rendered following a 

process that permanently alters that 

controlled substance’s physical or 

chemical condition or state through 

irreversible means and thereby renders 

the controlled substance unavailable 

and unusable for all practical 

purposes.’’ The regulation further 

provides that ‘‘a controlled substance is 

considered non-retrievable when it 

cannot be transformed to a physical or 

chemical condition or state as a 

controlled substance or controlled 

substance analogue,’’ and that ‘‘the 

purpose of destruction is to render the 

controlled substance(s) to a nonretrievable state and thus prevent 

diversion of any such substance to illicit 

purposes’’ (21 CFR 1300.05(b)). 

Under DEA regulations, an entity 

registered with the DEA 4 may collect 

controlled substances from ultimate 

users, to include collection by mail-back 

packages or envelopes, for the purpose 

of destruction.5 To be considered 

‘‘destroyed,’’ a mail-back package must 

be destroyed in compliance with 

applicable Federal, State, tribal, and 

local laws and regulations and must be 

rendered non-retrievable.6 Mail-back 

envelopes dispensed with opioid 

analgesics pursuant to a mail-back 

program that operates in compliance 

with DEA regulations and all other 

applicable laws would be ‘‘for the 

purposes of rendering the drug 

nonretrievable,’’ as required by section 

505–1(e)(4) of the FD&C Act. There are 

multiple companies that operate DEAregistered mail-back programs and have 

mail-back envelopes commercially 

available, which could be utilized by 

drug manufacturers who would be 

subject to the potential REMS 

requirement described in this notice. 

D. Mail-Back Envelopes in the Current 

Landscape of Opioid Disposal Options 

There are various options for safely 

disposing of opioid analgesics available 

to patients, all of which can achieve the 

goal of removing the risks associated 

with having unused and unsecured 

opioids stored in the home. There are 

both in-home disposal options (e.g., 

flushing, commercially available inhome disposal products) and disposal 

options outside of the home (i.e., 

collection kiosks, take-back events). 

FDA currently recommends disposing of 

opioids in permanent collection sites 

(e.g., kiosks in pharmacies) or at takeback events (Ref. 27). If these disposal 

options are not readily available, FDA 

recommends either flushing (for opioids 

on FDA’s ‘‘Flush List’’ (Ref. 28) or 

mixing with an unpalatable substance 

and disposing in household trash (Ref. 

27). 

However, each option has its own 

challenges, which can result in 

individuals being unable, unwilling, or 

reluctant to use them. For example, 

collection sites (e.g., kiosks) require 


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7 21 CFR 1317.70(c)(4). DEA added this 

requirement because it believed that ‘‘pre-paid 

postage will ensure that the package is not returned 

to sender, which will help reduce its handling and 

therefore, the diversion risks’’ (79 FR 53520 at 

53536, September 9, 2014). 

8See 21 CFR 1317.70; USPS Publication 52, Mailback programs. 

9Mail-back collectors are required to provide 

mail recipients with readymade packaging and 

labels that comply with USPS regulations for 

mailing controlled substances, including unique 

Intelligent Mail package barcodes. See USPS 

Publication 52, Mail-back programs. 

10See 21 CFR 1317.70(a); 1317.90(a). 

individuals to bring opioid analgesics 

out of the home to a public place, either 

a pharmacy or law enforcement facility. 

This requires planning, access to 

transportation, and follow-through. 

Some individuals are unable to readily 

or easily travel to a collection site. In 

addition, some individuals may be 

reluctant to bring opioid analgesics to a 

public location due to social stigma, or 

may fear entering law enforcement 

locations, especially while carrying 

opioid analgesics. 

In-home disposal options also have 

challenges. Many patients are reluctant 

to flush opioids (or other medications) 

due to environmental concerns (Ref. 28). 

FDA’s recommendation to mix some 

opioids (i.e., those not on the ‘‘flush 

list’’) with an unpalatable substance and 

dispose in household trash is a 

multistep process some patients may be 

unwilling or reluctant to undertake. In 

addition, disposal of opioids in 

household trash may not prevent all 

accidental exposures. 

Commercially available in-home 

disposal products (e.g., DisposeRx 

packets or Deterra kits) commonly 

dispensed by some pharmacies are 

another option, but they also require 

multiple steps (e.g., emptying pills from 

one container into another container, 

adding water, shaking to mix contents, 

disposing in household trash) (Refs. 29 

to 31), and some individuals may be 

reluctant to use them due to 

environmental concerns. Further, FDA’s 

understanding is that these products 

may not render drugs ‘‘nonretrievable’’ 

within the meaning of the DEA 

regulation referenced in section 505– 

1(e)(4)(B). Mail-back envelopes require 

individuals to put the mail-back 

envelopes in a mailbox, which, for some 

individuals, may be physically 

distanced from their home (e.g., 

apartments, P.O. boxes, Native 

American reservations). Additionally, 

patients may be reluctant to put opioids 

in the mail for fear of diversion (Ref. 

32). Some individuals may be more 

inclined to use one option; others a 

different option. Accordingly, FDA 

believes it is important to provide 

patients with a range of reasonable 

options, and to provide appropriate 

education on each of these options. 

FDA is aware that many 

organizations, both public and private, 

have ongoing efforts to increase safe 

disposal of unused opioids. For 

example, large retail pharmacy chains 

and many independent pharmacies 

operate drug disposal programs that 

include making drug disposal kiosks 

available in pharmacies, sponsoring 

drug ‘‘take-back’’ days and providing inhome disposal products (Refs. 33 to 37). 

It is our understanding that pharmacists 

often are instructed to counsel patients 

and include educational materials about 

safe disposal in conjunction with 

providing in-home disposal products. 

Some States and municipalities have 

passed legislation requiring 

manufacturers who sell drugs in their 

jurisdictions to fund drug disposal 

programs that can include subsidizing 

kiosks in pharmacies and/or the 

provision of in-home disposal products, 

including, occasionally, mail-back 

envelopes (Refs. 38 to 40). 

The Agency believes it is important 

for patients to have multiple options for 

disposing of unused opioids, including 

kiosks, take-back events, and in-home 

disposal options. Mail-back envelopes 

are one option that has multiple 

favorable characteristics. They do not 

require patients to mix medications 

with water, chemicals, or other 

substances. Mail-back envelopes are 

also required to be postage paid,7

thereby providing patients with a free 

disposal option. Further, most patients 

can mail these envelopes from their 

home. Additionally, the DEA and the 

U.S. Postal Service (USPS) have 

regulations and policies to ensure that 

mail-back envelopes are fit for purpose.8

The USPS has longstanding policies in 

place to safely and securely transport 

mail-back envelopes to the location 

where they will be destroyed.9 Finally, 

unlike other alternatives described here, 

the DEA requires mail-back envelopes to 

be disposed of in a manner that renders 

them non-retrievable,10 which is 

typically accomplished through 

incineration. As a result, mail-back 

envelopes (along with collection kiosks) 

result in less opioids in the water 

supply and landfills than is associated 

with other disposal options. 

FDA recognizes that, notwithstanding 

these benefits, mail-back envelopes are, 

at present, relatively underutilized. 

Large retail pharmacy chains have 

focused on take-back days, kiosks, and 

a provision of commercially available 

in-home disposal products (Refs. 33 to 

37), while it appears manufacturers 

subject to State-mandated disposal 

requirements have primarily focused on 

collection kiosks. FDA anticipates that a 

REMS-mandated disposal program for 

opioid analgesics focused on provision 

of mail-back envelopes, together with 

education on multiple safe disposal 

options, could complement these 

existing opioid disposal programs. 

E. Approach Under Consideration: MailBack Envelopes and Education on 

Proper Disposal Must Be Provided to 

Patients With Opioid Analgesics 

Dispensed in Outpatient Pharmacies 

FDA is considering adding a mailback envelope requirement to the OA 

REMS to require that all opioid 

analgesics, including immediate-release 

(IR), extended-release (ER), and longacting (LA) formulations, used in the 

outpatient setting that are subject to the 

OA REMS be dispensed with mail-back 

envelopes. 

Although most studies reported 

excess opioid analgesics after a surgical 

procedure (Refs. 10 and 11), suggesting 

the need to target disposal options for 

patients with acute pain, the pharmacist 

at the time of dispensing may find it 

difficult to differentiate whether a 

patient is being treated for acute or 

chronic pain. For example, using 

specific formulations of opioid 

analgesics as a proxy for distinguishing 

between acute or chronic pain would 

not be appropriate because patients with 

chronic pain may take both IR and ER 

or LA formulations. In fact, most 

patients receiving an opioid analgesic, 

regardless for how long, use IR 

formulations (Ref. 41). Further, as 

mentioned above, opioid analgesics 

prescribed for chronic pain can also 

become unneeded. Therefore, FDA is 

considering having any mail-back 

envelope requirement apply to all 

opioid analgesics, including IR, ER, and 

LA formulations, used in the outpatient 

setting for acute or chronic pain that are 

subject to the OA REMS. 

That said, requiring that a mail-back 

envelope be dispensed with every 

opioid analgesic prescription could be 

inefficient and lead to an excess of 

dispensed mail-back envelopes. The use 

of algorithms to target mail-back 

envelope distribution in a thoughtful, 

tailored manner would be expected to 

positively impact program fidelity and 

outcomes and decrease waste. Some 

existing retail pharmacy programs that 

provide disposal options to patients use 

algorithms to target disposal options to 

certain patients or certain 

circumstances, such as only providing 

disposal options every 6 months to 

patients who continue to fill multiple 

opioid analgesic prescriptions (Refs. 33 

and 34). Other potential algorithms 


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11 21 CFR 1317.70(c)(1); USPS Publication 52, 

Mail-back programs. 

could target the provision of mail-back 

envelopes to patients filling a 

prescription for an amount of opioids 

generally consistent with acute pain 

treatment, or to patients with a change 

in dose of a recurring opioid analgesic 

prescription who may then have unused 

opioids. FDA recognizes that the 

upfront effort to implement algorithms 

could be complicated but expects that 

the use of algorithms would be more 

efficient and would reduce the longterm burden on the healthcare delivery 

system by targeting the distribution of 

mail-back envelopes to patients most 

likely to have unused opioids. FDA 

would appreciate input on appropriate 

optimal algorithm design for a potential 

targeted mail-back envelope provision. 

We would also expect, regardless of the 

algorithm used, that mail-back 

envelopes would be provided to any 

patient or caregiver who requests one. 

Additionally, we would expect that if a 

given patient does not want the mailback envelope, they could decline the 

offer. 

Multiple studies we reviewed 

indicated that unused opioids are often 

stored in unsecure locations (Ref. 10) 

and that patients were reluctant to 

dispose of unused opioid analgesics for 

various reasons, including the patient’s 

belief that they might need the unused 

opioids in the future (Refs. 32, 42, and 

43). In the studies that we reviewed, 

patient and caregiver education about 

disposal was often provided with an athome disposal option during counseling 

about care after a procedure, and 

patients were reminded about disposal 

during followup contacts. For example, 

one study found that combining an inhome disposal option with patient 

education focused on the importance of 

disposal increased the disposal rate 

versus simply providing an in-home 

disposal option or patient education 

(Ref. 23). Accordingly, we believe that 

patient and caregiver education that 

explains the importance of safe storage 

and proper disposal and addresses 

patients’ reluctance to dispose of 

opioids would be an integral component 

of any mail-back envelope REMS 

requirement. We also believe that takehome educational materials on proper 

disposal, as well as followup reminders 

(e.g., automated text messages), are 

likely to have a positive reinforcing 

effect on patient counseling provided by 

the pharmacist at the time of 

dispensing. 

There are multiple ways a mail-back 

envelope REMS requirement could be 

designed and operationalized. We 

describe two possibilities here, and 

welcome input on others. One option 

would be to require that drug 

manufacturers subject to the OA REMS 

make mail-back envelopes available to 

outpatient pharmacies at no cost and 

allow pharmacies to provide mail-back 

envelopes and counseling on disposal 

according to their own policies and 

procedures. Additionally, to encourage 

patient education, FDA may also require 

manufacturers to create educational 

materials to assist pharmacists in 

counseling patients on safe storage and 

proper disposal. However, this option 

would not require that pharmacies 

actually provide mail-back envelopes, 

counseling on disposal, or take-home 

educational materials. As such, this 

option would ultimately rely on 

pharmacy policies and procedures to 

drive the use of mail-back envelopes 

and counseling on safe disposal. 

Alternatively, FDA could require 

manufacturers to only distribute opioids 

to outpatient pharmacies certified in the 

REMS. Certification could require that 

mail-back envelopes, patient 

counseling, take-home materials, and 

followup reminders (e.g., text messages) 

be provided according to the terms of 

the REMS, and that all of these activities 

be conducted and appropriately 

documented. Again, manufacturers 

would supply mail-back envelopes to 

pharmacies at no cost. Certification of 

pharmacies could include requiring 

pharmacy staff to complete specified 

training on how to counsel patients on 

safe storage and proper disposal. As 

with the first option, FDA may also 

require manufacturers to create 

educational materials to assist 

pharmacies with patient counseling. 

For any mail-back envelope REMS 

requirement, FDA would intend for the 

program to increase the quantity of 

unused opioids properly disposed of, 

and, therefore, to decrease the quantity 

of unused opioids available for 

nonmedical use, accidental exposure, 

and overdose. FDA anticipates the 

potential for greater impact with the 

second option than the first but 

acknowledges that the second option 

would impose greater burdens on the 

healthcare system. 

The potential burdens associated with 

a mail-back envelope REMS 

requirement on pharmacies and 

pharmacists would include, depending 

on the program design: (1) Completion 

of any REMS-mandated training and 

certification; (2) implementation of 

REMS-compliant processes in 

pharmacies; and (3) documentation of 

compliance with REMS requirements by 

pharmacies. These efforts are in 

addition to existing State and Federal 

pharmacy requirements associated with 

dispensing opioids (e.g., checking 

prescription drug monitoring programs). 

A mail-back envelope REMS 

requirement is likely to be more 

effective under the second scenario 

described above. However, the more 

requirements the REMS imposes, the 

more likely that relevant stakeholders, 

particularly pharmacies, will have 

challenges complying with the 

requirements. Ensuring the 

requirements are met may necessitate 

remediation steps, such as reeducation, 

or even decertification, if a pharmacy 

fails to comply. Declining to certify or 

decertifying a pharmacy could affect 

patients’ access to appropriately 

prescribed opioid analgesics. 

Accordingly, the ability of potential 

OA REMS disposal requirements to be 

integrated into healthcare providers’ 

existing workflow is an important 

consideration in FDA’s decision 

making. The Agency is seeking input on 

the design of a potential mail-back 

envelope REMS requirement that strikes 

the right balance between positive 

impact on unused opioid analgesic 

disposal and burden on pharmacies and 

other stakeholders. 

F. Other Considerations for Requiring 

Provision of Mail-Back Envelopes With 

Opioid Analgesics 

Current DEA and USPS regulations 

and policies require mail-back 

envelopes to be nondescript, i.e., they 

must not include any markings or other 

information that might indicate that the 

package contains controlled 

substances.11 These specifications help 

alleviate concerns that mail-back 

envelopes can easily be identified for 

diversion while in transit. However, if a 

potential mail-back envelope REMS 

requirement were implemented, it could 

be expected to greatly increase the 

number of mail-back envelopes in 

circulation. The USPS has informed the 

Agency that the existing regulatory 

scheme, as well as USPS’ rigorous 

monitoring and policing mechanisms, 

should be adequate to accommodate an 

increase in mail-back envelope 

utilization. We welcome other 

stakeholder views on this issue, 

including how any potential adverse 

consequences could be mitigated. 

FDA expects that a mail-back 

envelope OA REMS requirement would 

provide patients with an additional 

disposal option that complements 

disposal options already available 

through ongoing public and private 

efforts. The Agency understands mailback envelopes will not be the preferred 

disposal option for all patients. FDA’s 

expectation is that existing disposal 


jspears on DSK121TN23PROD with NOTICES1
23874 Federal Register / Vol. 87, No. 77 / Thursday, April 21, 2022 / Notices 

programs (e.g., provision of in-home 

disposal options by many pharmacies, 

including most major chain pharmacies) 

will continue, such that a mail-back 

envelope mandate would provide 

patients with an additional disposal 

option without affecting other existing 

disposal options. We are seeking input 

on how a mail-back envelope OA REMS 

requirement could be designed and 

operationalized to complement existing 

disposal efforts and programs. 

G. Other Actions That Could 

Complement a Mail-Back Envelope 

REMS Mandate 

FDA is considering additional actions 

that may be necessary or appropriate if 

we were to impose a mail-back envelope 

disposal requirement under the OA 

REMS. For example, FDA would need to 

amend recommendations in the 

‘‘Remove the Risk’’ campaign on safe 

disposal of opioids to include 

information on the availability and use 

of mail-back envelopes (Ref. 44). 

Likewise, FDA would need to amend 

the information on disposal in FDAapproved prescriber and patient labeling 

for opioids that would be subject to the 

mail-back envelope REMS requirement, 

as this labeling currently does not 

mention mail-back envelopes. FDA is 

also considering whether it might be 

appropriate to have a large media 

campaign aimed at increasing public 

awareness of the importance of 

promptly disposing unused opioids and 

how to safely dispose of them. FDA 

welcomes input on these and any other 

potential actions that could increase the 

effectiveness of a mail-back envelope 

disposal requirement under the OA 

REMS. 

III. Additional Request for Comments 

And Information 

FDA is soliciting comments from 

stakeholders regarding all aspects of the 

potential mail-back envelope REMS 

mandate described in this document. 

The Agency is particularly interested in 

comments on the following topics: 

1. The potential safety advantages and 

public health impacts of providing mailback envelopes with opioid analgesics 

dispensed in an outpatient setting. 

2. Whether there are specific opioid 

analgesic drug products for which 

requiring mail-back envelopes is more 

important from a public health 

perspective and, if so, which products. 

3. How pharmacies could identify 

those patients who are most likely to 

have unused opioids to optimize 

provision of mail-back envelopes to 

these patients and potentially positively 

impact the share of mail-back envelopes 

that are utilized to safely dispose of 

opioid analgesics. 

4. How pharmacies could develop and 

implement algorithms to determine 

when to provide a mail-back envelope, 

including how feasible or practical it 

would be for pharmacies to do so. 

5. Whether requiring provision of 

mail-back envelopes under the OA 

REMS should also include a 

requirement for patient counseling and/ 

or provision of take-home materials on 

safe disposal at the point of dispensing. 

6. What key educational messages 

regarding secure storage and safe 

disposal should be included in any 

patient education component of the 

potential OA REMS requirement 

described in this notice, including 

educational messages to increase uptake 

and use of mail-back envelopes, as well 

as what form that education should take 

(e.g., handouts, pharmacist counseling 

of patients). 

7. How a mail-back envelope 

requirement could be designed and 

implemented to help ensure that the 

disposal requirement minimizes burden 

on pharmacies while still providing the 

public health benefit. As discussed in 

the document, there is a tradeoff 

between the potential effectiveness of a 

mail-back envelope REMS requirement 

and the level of burden imposed on 

those pharmacies involved in 

implementing the requirement. 

8. Possible challenges, including 

technical and logistical challenges, with 

the potential REMS mandate described 

in this notice, and what factors could 

impact manufacturers’ ability to provide 

mail-back envelopes to pharmacies, or 

the ability of pharmacies to dispense 

mail-back envelopes and provide 

appropriate disposal education to 

consumers. 

9. The impact of a mail-back envelope 

REMS requirement on other 

stakeholders, including manufacturers, 

prescribers, payers, and patients. 

10. How a mail-back envelope REMS 

requirement could be designed and 

operationalized to provide another 

option for patients that would 

complement current pharmacy disposal 

programs, policies, and procedures, as 

well as Federal, State, local, and private 

sector efforts on proper opioid disposal. 

11. Possible negative impacts of a 

potential mail-back envelope REMS 

mandate, including whether there is a 

risk that it could diminish the impact of 

other public and private efforts around 

safe disposal. For example, could it be 

the case that for some patients, 

provision of a mail-back envelope 

together with another commercially 

available in-home disposal product, and 

education on how to use both, could be 

overwhelming and lead to less 

comprehension and utilization of either 

option? 

12. How manufacturers and FDA 

could best assess the effectiveness of a 

mail-back envelope OA REMS 

requirement. Assessing the impact of a 

mail-back envelope requirement in a 

REMS is likely to be challenging 

because, among other reasons, current 

DEA regulations prohibit mail-back 

envelopes from being opened prior to 

destruction, preventing a direct 

inventory of contents; and some of the 

opioids disposed of in mail-back 

envelopes would presumably be 

disposed of using another disposal 

option if the mail-back envelope were 

not provided. 

13. How patients and others may 

perceive the environmental impact of a 

potential mail-back envelope 

requirement, including the potential for 

such envelopes to reduce the amount of 

medications flushed or disposed of in 

landfills. 

14. Any existing programs that 

provide mail-back envelopes, especially 

programs that provide patient 

counseling on disposal and that operate 

in retail pharmacies, including any data 

on the effectiveness of these programs. 

15. Section 3032 of the SUPPORT Act 

authorizes the Agency to use its REMS 

authority to require that a safe disposal 

packaging or safe disposal system for 

the purposes of rendering the drug 

nonretrievable be dispensed to certain 

patients with drugs that pose a serious 

risk of abuse or overdose if, among other 

things, FDA determines that such safe 

disposal packaging or system may 

mitigate such risks and is sufficiently 

available (21 U.S.C. 355–1(e)(4)). We 

recognize that the approach described in 

this document is only one potential use 

of the Agency’s REMS authority 

concerning disposal. Comment on other 

possible uses of the Agency’s REMS 

authority concerning disposal, 

including providing any data or 

information about whether other 

disposal packaging or disposal systems 

we might consider mandating, such as 

commercially available in-home 

disposal products, would satisfy the 

statutory requirements at 21 U.S.C. 355– 

1(e)(4). 

16. Discuss other actions FDA could 

take in addition to, and in support of, 

a mail-back envelope disposal REMS 

requirement to increase safe disposal of 

unused opioid analgesics. 

IV. References 

The following references marked with 

an asterisk (*) are on display at the 

Dockets Management Staff (see 

ADDRESSES) and available for viewing by 


jspears on DSK121TN23PROD with NOTICES1
Federal Register / Vol. 87, No. 77 / Thursday, April 21, 2022 / Notices 23875 

interested persons between 9 a.m. and 4 

p.m., Monday through Friday; they also 

are available electronically at https://

www.regulations.gov. References 

without asterisks are not on public 

display at https://www.regulations.gov 

because they have copyright restriction. 

Some references may be available at the 

website address, if listed. References 

without asterisks are available for 

viewing only at the Dockets 

Management Staff. FDA has verified the 

web addresses, as of the date this 

document publishes in the Federal 

Register, but websites are subject to 

change over time. 

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default/files/reports/rpt29393/ 

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28 (February 2016): 106–112. 

4. Surratt, H.L., S.P. Kurtz, M. Buttram, et al. 

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November 23, 2021. 

Dated: April 13, 2022. 

Lauren K. Roth, 

Associate Commissioner for Policy. 

[FR Doc. 2022–08372 Filed 4–20–22; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

National Institutes of Health 

National Institute of Dental & 

Craniofacial Research; Notice of 

Closed Meeting 

Pursuant to section 10(d) of the 

Federal Advisory Committee Act, as 

amended, notice is hereby given of the 

following meeting. 

The meeting will be closed to the 

public in accordance with the 

provisions set forth in sections 

552b(c)(4) and 552b(c)(6), Title 5 U.S.C., 

as amended. The grant applications and 

the discussions could disclose 

confidential trade secrets or commercial 

property such as patentable material, 

and personal information concerning 

individuals associated with the grant 

applications, the disclosure of which 

would constitute a clearly unwarranted 

invasion of personal privacy. 

Name of Committee: National Institute of 

Dental and Craniofacial Research Special 

Emphasis Panel; Summer Research 

Education R25 and DSR Member Conflict 

SEP. 

Date: June 17, 2022. 

Time: 11:00 a.m. to 5:00 p.m. 

Agenda: To review and evaluate grant 

applications. 

Place: National Institute of Dental & 

Craniofacial Research, 6701 Democracy 

Blvd., Bethesda, MD 20817 (Virtual Meeting). 

Contact Person: Aiwu Cheng, Ph.D., 

Scientific Review Officer, Scientific Review 

Branch, Division of Extramural Activities 

National Institute of Dental & Craniofacial 

Research, National Institutes of Health, 6701 

Democracy Blvd., Bethesda, MD 20892, 

Aiwu.cheng@nih.gov. 

(Catalogue of Federal Domestic Assistance 

Program No. 93.121, Oral Diseases and 

Disorders Research, National Institutes of 

Health, HHS) 

Dated: April 18, 2022. 

Melanie J. Pantoja, 

Program Analyst, Office of Federal Advisory 

Committee Policy. 

[FR Doc. 2022–08522 Filed 4–20–22; 8:45 am] 

BILLING CODE 4140–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

National Institutes of Health 

Center for Scientific Review; Notice of 

Closed Meeting 

Pursuant to section 10(d) of the 

Federal Advisory Committee Act, as 

amended, notice is hereby given of the 

following meeting. 

The meeting will be closed to the 

public in accordance with the 

provisions set forth in sections 

552b(c)(4) and 552b(c)(6), Title 5 U.S.C., 

as amended. The grant applications and 

the discussions could disclose 

confidential trade secrets or commercial 

property such as patentable material, 

and personal information concerning 

individuals associated with the grant 

applications, the disclosure of which 

would constitute a clearly unwarranted 

invasion of personal privacy. 

Name of Committee: Center for Scientific 

Review Special Emphasis Panel; Health 

Services Organization, Delivery, Quality and 

Effectiveness. 

Date: May 4, 2022. 

Time: 11:00 a.m. to 1:00 p.m. 

Agenda: To review and evaluate grant 

applications. 

Place: National Institutes of Health, 

Rockledge II, 6701 Rockledge Drive, 

Bethesda, MD 20892 (Virtual Meeting). 

Contact Person: Wenjuan Wang, Ph.D., 

Scientific Review Officer, Center for 

Scientific Review, National Institutes of 

Health, 6701 Rockledge Drive, Room 3154, 

Bethesda, MD 20892, (301) 480–8667, 

wangw22@mail.nih.gov. 

This notice is being published less than 15 

days prior to the meeting due to the timing 

limitations imposed by the review and 

funding cycle. 

(Catalogue of Federal Domestic Assistance 

Program Nos. 93.306, Comparative Medicine; 

93.333, Clinical Research, 93.306, 93.333, 

93.337, 93.393–93.396, 93.837–93.844, 

93.846–93.878, 93.892, 93.893, National 

Institutes of Health, HHS) 

Dated: April 15, 2022. 

Tyeshia M. Roberson-Curtis, 

Program Analyst, Office of Federal Advisory 

Committee Policy. 

[FR Doc. 2022–08500 Filed 4–20–22; 8:45 am] 

BILLING CODE 4140–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

National Institutes of Health 

Center for Scientific Review; Notice of 

Closed Meetings 

Pursuant to section 10(d) of the 

Federal Advisory Committee Act, as 

amended, notice is hereby given of the 

following meetings. 


jspears on DSK121TN23PROD with NOTICES1