U.S. Department of  Health and Human  Services  
 
Office of Inspector General 
 
 
 
FDAs Risk Evaluation and 
Mitigation Strategies:  
Uncertain Effectiveness in 
Addressing the Opioid Crisis 
 
 
Suzanne Murrin 
Deputy Inspector General for Evaluation and Inspections 
September 2020, OEI-01-17-00510   U.S. Department of Health and Human Services 
O  ffice of Inspector General 
 
Report in Brief 
 
Se ptember 2020, OEI-01-17-00510 
 
FDAs Risk Evaluation and Mitigation 
Why OIG Did This Review 
While the opioid crisis continued  Strategies: Uncertain Effectiveness in 
with nearly 47,000 deaths in 2018, 
Addressing the Opioid Crisis  
the Food and Drug Administration  
(FDA) used Risk Evaluation  and 
Mitigation Strategies (REMS) as   The Food and Drug Administration (FDA) 
tools to mitigate misuse and abuse  Key Takeaways  can require drug manufacturers to 
of opioids.  REMS have the   develop and implement a Risk Evaluation 
Although opioid prescribing 
potential to help address the  and Mitigation Strategy (REMS) to ensure 
has decreased, data quality 
opioid crisis, but previous Office of  that the benefits of a drug outweigh its 
issues have made it 
Inspector General work from 2013  risks.  A REMS is a drug safety program 
challenging for FDA to 
raised concerns  about FDAs  that is intended to mitigate a specific 
determine whether the two  
oversight and the overall  serious risk associated with the use of a 
REMS for opioids have been 
effectiveness of REMS programs.   drug.  FDA can require a REMS if it 
effective.  Furthermore, REMS  
This review determines the extent   determines that placing a drugs risks on 
may not be well-suited to 
to which FDA has held drug  the FDA-approved drug label is 
quickly address the opioid 
manufacturers accountable for  insufficient to protect patients.  FDA  
crisis.  
mitigating the risk of opioid misuse  specifies the requirements and approves  
and abuse through REMS.  It   the REMS.  However, the drug manufacturer is responsible for developing 
complements OIGs past work  and implementing the program.  Following approval of the REMS, the 
tracking opioid use among  manufacturers submit assessments detailing how the REMS is performing 
Medicare and Medicaid   and whether it is meeting its goals to FDA.   
beneficiaries and provides insight 
into the Federal response to the  Transmucosal immediate-release fentanyl (TIRF) drugs and extended-
national opioid crisis.   release/long-acting (ER/LA) opioids are two major classes of opioids that 
pose serious risk of addiction, abuse,  and overdose.  In 2011 and 2012, FDA 
How OIG Did This Review  approved the REMS for TIRF drugs and the REMS for ER/LA opioids, 
We analyzed documents related to  respectively, just as opioid prescribing reached its peak.  The two REMS are 
the REMS for transmucosal  intended to mitigate risks of abuse and misuse while maintaining access to  
immediate-release fentanyl (TIRF)  these two classes of opioids.  These REMS represent important pieces of the 
and extended-release/long-acting  Federal efforts to address the opioid public health crisis.  
opioids (ER/LA) from 2011 through 
2017, including all drug  What OIG Found 
manufacturer-submitted  While the severity of the opioid crisis became more  apparent over time and 
assessments, FDA decision   the Federal Government and States launched initiatives to combat opioid 
memoranda, assessment reviews,  abuse, FDA struggled to measure the effectiveness of the REMS for TIRF  
inspection reports, and other  drugs and for ER/LA opioids in mitigating the misuse of opioids. 
analyses and correspondence.  We  
For the REMS for TIRF drugs, FDA found data in the assessments suggesting 
also interviewed FDA staff about 
that the manufacturers were not meeting all their goals and also found the 
REMS oversight.  
data for some of the REMS goals to be inadequate.  From 2014 to 2017, FDA 
consistently responded to its concerns about the data by requesting better 
data from the TIRF drug manufacturers or conducting its own analysis.  In 
2019, FDA announced  a proposed modification to the TIRF REMS that places 
a greater emphasis on ensuring that patients who  are prescribed TIRF drugs 
    are opioid-tolerant, including required documentation and a patient registry 
to capture needed data.  However, the new goals no longer say that TIRF 
drugs should be prescribed and dispensed only to appropriate patients (i.e., 
patients with breakthrough cancer pain), which may signal to prescribers that  
prescribing TIRF drugs off-label to treat patients with wide-ranging pain 
symptoms (i.e., low-level chronic pain, post-operative acute pain, etc.) is 
appropriate.  
Similarly, in assessments from 2014 through 2017, poor data left FDA unable 
to determine whether the REMS for ER/LA opioids was meeting its 
overarching goal of reducing serious  adverse outcomes resulting from 
inappropriate prescribing, misuse, and abuse of the drugs.  However, FDA did 
find that manufacturers repeatedly missed the REMS targets for training  
prescribers.  As it did with the TIRF REMS, FDA requested that manufacturers 
of ER/LA opioids submit more and better data from different sources.  
However, FDA was often so late in providing its reviews to the manufacturers 
that manufacturers had no time to respond to FDAs concerns before  their 
next assessments were due.  Finally, in 2018 FDA modified the REMS goals for 
ER/LA opioids, moving away from an attempt to measure outcomes to 
measuring voluntary prescriber training meant to educate prescribers about 
risks.  
FDA faced additional challenges to ensuring that these REMS mitigate opioid 
misuse and abuse.  In addition to limitations in the data from the drug 
manufacturers, FDA faced measurement challenges, such as a lack of baseline 
data, limited surveillance data, and the inability to distinguish the effects of 
the REMS separate from the other initiatives addressing opioid misuse and 
abuse.  Some opioid manufacturers engaged in deceptive marketing 
practices that undermined the REMS educational messages regarding risk.  
Furthermore, the fact that both REMS are what is known as shared system 
REMSmeaning that they aggregate their data across drugs and product 
categoriescan mask problems with individual drugs or product categories.  
Finally, FDA has limited authority to enforce manufacturers compliance with 
their REMS.  
What OIG Recommends and How the Agency Responded 
The opioid crisis has  cost the United States hundreds of thousands of lives  
and billions of dollars.  Although opioid prescribing has decreased by 34 
percent since 2012, opioids are still heavily prescribed, and overdoses have 
continued to claim thousands of lives annually.   
Among its other efforts to combat this public health emergency, FDA has 
used REMS to help mitigate the risk posed by opioids.  On the basis of our 
review, REMS are not well-suited to quickly address the opioid crisis.  The 
REMS for TIRF drugs and ER/LA opioids both rely largely on educating 
prescribers about the risks of these drugs.  This takes time to have an impact 
on prescribing habits and can be countered by pharmaceutical marketing 
campaigns designed to increase prescribing.  In addition, FDAs deliberate  
approach to decision-making, which relies on scientifically robust data, 
focused FDAs attention for years on improving the serious data-quality 
issues.  
    While FDA and other agencies in HHS continue to  address the opioid crisis 
using a variety of efforts, OIG has the following recommendations for FDA to 
improve these two opioid REMS: 
 
 use the new TIRF REMS patient registry to monitor for known areas of risk, 
such as inappropriate conversions (i.e., switching a patient between 
different TIRF drugs inappropriately) and off-label prescribing;   
 strengthen the REMS for opioid analgesics (the successor to the REMS for 
ER/LA opioids) by requiring training for prescribers;  
 enhance its REMS assessment review process by  completing its reviews in a 
timely fashion and seeking information on inappropriate prescribing trends 
from FDAs Office of Prescription Drug Promotion; and finally,  
 seek additional authority to ensure that manufacturers  are held  
accountable when appropriate.  
 
FDA concurred with our first and third recommendations.  It did not concur 
with our second recommendation.  It is considering our fourth 
recommendation.  
 
Full report: oig.hhs.gov/oei/reports/oei -01- 17-00510.asp   TABLE OF CONTENTS 
BACKGROUND   1 
Methodology   6 
FINDINGS   8 
FDAs reviews raised questions about the effectiveness of the REMS for TIRF drugs, but data  8 
quality affected timely  oversight  
After being unable to determine whether the REMS for ER/LA opioids reduced adverse  14  
outcomes, FDA modified the REMS goal to focus instead on educating prescribers  
FDA faces challenges to ensuring that REMS mitigate opioid misuse and abuse   17  
CONCLUSION AND RECOMMENDATIONS  20  
Use the new TIRF REMS patient registry to monitor for known areas of risk, such  as       20  
inappropriate conversions and off-label prescribing 
Strengthen the REMS  for opioid analgesics  (the successor to the REMS for ER/LA opioids) by  21  
mandating prescriber training 
Enhance its REMS  assessment review process   22  
Seek additional authority to ensure that manufacturers are held accountable when  22  
appropriate  
AGENCY COMMENTS AND OIG RESPONSE    23  
APPENDICES    25  
A.  Requirements of the REMS for ER/LA opioids and for TIRF drugs, by assessment period   25  
B.  Results of knowledge surveys required by the REMS for TIRF drugs failed to meet  27  
performance goals  
C.  REMS for ER/LA opioids: Timeline for manufacturer submissions and FDA reviews, July 2014 28  
through February  2018 
D.  Agency Comments   29  
ACKNOWLEDGMENTS AND CONTACT  36  
ABOUT THE OFFICE OF INSPECTOR GENERAL  37  
ENDNOTES    38    
BACKGROUND 
 
 
Objective  
To determine the extent to which FDA held drug manufacturers accountable for 
mitigating the risk of opioid misuse and abuse through Risk Evaluation and 
Mitigation Strategies (REMS).  
 
Opioids are powerful, pain-relieving drugs that must be prescribed and used carefully 
to ensure that their benefits outweigh their risks.  Public health experts believe that 
opioids have been overprescribed since the drugs first became prominent in the mid-
1990s.  Recent State court settlements have held opioid drug manufacturers 
accountable for damages resulting from deceptive opioid marketing that started in 
the mid-1990s.1   
The widespread  overprescribing of opioids in the United States led to increases in 
opioid-related deaths and opioid dependence treatment.2  According to the Centers 
for Disease Control and Prevention (CDC), more than 232,000 people in the United 
States died from prescription opioid-related overdoses between 1999 and 2018.3  In  
2018, nearly  47,000 people in the United Statesan average of 128 people a day
died of opioid-related overdoses, with a quarter of those overdose deaths involving 
prescription opioids.4  In  2017, the Acting Secretary of Health and Human Services 
declared the opioid epidemic a national public health emergency.5  Added to the toll 
in lives is an economic tollresearchers estimate that the economic burden from 
opioid misuse and abuse in the Unites States exceeds $78 billion annually.6  
Within the U.S. Department of Health and Human Services, the Food and Drug 
Administration (FDA) can play a significant role in the Federal effort to combat opioid 
abuse.  FDAs efforts to address the opioid public  health crisis include, but are not 
limited to, the following: (1) requiring safety-related labeling changes for the 
extended-release/long-acting (ER/LA) opioid analgesics;  (2) requiring manufacturers 
of ER/LA opioids to formally study the adverse outcomes of abuse, misuse, addiction, 
overdose, and death among patients prescribed long-term opioid therapy; 
(3) expanding access to naloxone (a drug that can reverse opioid overdoses); 
(4) promoting access to medication-assisted treatment for opioid addiction; 
(5) encouraging opioid formulations that deter abuse; and, (6) encouraging novel, 
nonopioid treatments for pain.7  
Another tool that FDA has to address the opioid public health crisis is REMS, a drug 
safety program.  In 2007, after the drug rofecoxib (Vioxx) was associated with a high 
number of deaths from heart attack and stroke, Congress gave FDA the authority to 
require drug manufacturers (or companies that own an FDA-approved application) to 
develop REMS.8  Required by FDA for certain medications, a REMS is a structured plan 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Background | 1  that is intended to manage specific serious safety concerns.  The REMS for opioids are 
intended to mitigate the risk of misuse, abuse, addiction, accidental overdose, and 
death, while maintaining patient access to these medications.  This study focuses on  
the REMS for two classes of opioids: ER/LA opioids and transmucosal immediate 
release fentanyl (TIRF) drugs. 
Opioids and the REMS program  
Prescription Opioids  
Opioid analgesics approved for marketing in the U.S. come in a variety  of chemical  
formulations, strengths, and delivery systems.  For example, some opioids provide an 
analgesic effect over 24  hours or longer (extended release products), as opposed to 
immediate release opioids, which act more quickly and last only several hours.9   
Fentanyl, which is 50 to 100 times more powerful than morphine, is a fast-acting 
opioid approved for breakthrough cancer pain.10  Opioids can create a euphoric  
effect, which makes them vulnerable to abuse and misuse (i.e., taking them in a way 
other than prescribed).   
Although opioid prescribing has decreased 34 percent since its peak in 2012, 
providers prescribed about 80 percent more opioids in 2018 than they did during the 
1990s.11, 12  Experts believe that the long-term trend of overprescribing is a key factor 
that led to the current opioid crisis.13, 14  As awareness about the dangers of opioids 
increased among prescribers and patients, and prescribing decreased, patients who 
had become addicted to opioids sought heroin and illegally sourced fentanyl.  Drug 
overdose deaths reached a record high in 2017, driven largely by heroin and 
fentanyl.15  
FDAs REMS Program  
FDA may approve a drug for marketing in the United States if it is safe and effective 
for its intended use, although the drug may still have harmful or undesirable side 
effects.16  FDA considers a drug safe if its potential benefits outweigh its known and 
potential risks.  Routine measures, such  as FDA-approved prescribing information 
found on a drugs label, may help to ensure this balance for most drugs.  However, 
when there are serious safety  concerns about a drug, FDA can require a REMS to 
ensure that the benefits of the drug outweigh the risks.17  
A REMS is a drug safety  program that uses strategies beyond FDA-approved labeling 
and is intended to mitigate a specific, serious risk associated with the use of the drug.   
REMS can include a variety of elements intended to mitigate risk for a drug that 
would otherwise be unavailable due to known serious risks.18, 19  These REMS  
elements may include drug manufacturers providing FDA-approved training to 
prescribers, or restrictions on how  a drug should be prescribed.  When establishing 
the elements in a REMS, FDA considers the burden to the health care delivery system 
(for example, prescribers and pharmacies) and patient access to the drug.20  
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Background | 2   After FDA decides a REMS is necessary and specifies the requirements, it approves the 
REMS designed by  a drug manufacturer, who is responsible for implementing the 
program.21  The drug manufacturer is required to submit assessment reports 
(assessments) to FDA detailing the implementation and compliance with the 
requirements as well as the goals and subgoals (FDA refers to these as objectives).22   
Assessments may include updates from the drug manufacturer on its efforts to inform 
prescribers and other stakeholders about the risk of the drug.  The REMS  assessment 
also includes surveillance or other patient outcome data; results of surveys; results of 
audits; and other metrics as specified in the REMS assessment plan.   
FDAs goal is to review a manufacturers assessment within 6 months.23,  24  However, 
FDA told us that more complex assessments may require more time than that to 
thoroughly review and analyze the data submitted.  Multiple divisions within FDAs 
Center for Drug Evaluation take part in reviewing the assessments.25  FDA verifies all 
information that drug manufacturers submit, including statistical analyses, and 
decides whether to modify the REMS.   
Drug manufacturers of products that are in the same class of drug (e.g., a brand-name 
drug and its generic equivalents) may combine their efforts in what is known as a 
shared system REMS.  In  a shared system REMS, multiple drug manufacturers share in 
the implementation and structure of a single REMS, which aids efficiency and lessens 
the burden on individual manufacturers, as well as on prescribers and pharmacies.  
Within a shared system REMS, drug manufacturers may hire contractors to administer 
the plan and to aggregate data across all drugs within the class.  Such aggregated 
data may include utilization, adverse events, and survey data.  The REMS for ER/LA 
opioids and for TIRF drugs are both shared system REMS.  
REMS for TIRF drugs and ER/LA opioids 
TIRF Drugs  
TIRF drugs are short-acting, high-potency, opioid analgesics approved for 
breakthrough pain in cancer patients who are opioid-tolerant.26  TIRF drugs are 50 to 
100 times more powerful than morphine.  Because TIRF drugs are so potent, non-
opioid-tolerant patients who use this class of drugs are at an increased risk of life-
threatening respiratory depression.  Furthermore, because of the pharmacokinetic 
differences among TIRF drugs, prescribers should exercise care when converting 
between TIRF drugsi.e., when switching a patient from one TIRF drug to another
or the patient may have an increased risk of a fatal overdose.  Patients must also take 
care to prevent accidental exposure of TIRF drugs to anyone other than the patient, 
particularly children.  
 
 
 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Background | 3   Goals of the REMS for TIRF drugs  
The overarching goal of the TIRF REMS is to mitigate the risk of misuse, 
abuse, addiction, overdose, and serious complications due to medication 
errors by:  
  Prescribing and dispensing TIRF medicines only to appropriate 
patients, which includes use only in opioid-tolerant patients;  
  Preventing inappropriate conversion between TIRF medicines;  
  Preventing accidental exposure to children and others for whom 
[TIRF medicines were] not prescribed; and  
  Educating prescribers, pharmacists, and patients on the potential for 
misuse, abuse, addiction, and overdose of TIRF medicines.  
Source:  FDAs final review of REMS for TIRF drugs, 2011.  
 
FDA approved the shared system REMS  for TIRF drugs in 2011; it initially included five 
drugs produced by four drug manufacturers.27  Since 2015, FDA has modified the 
shared system TIRF REMS to include nine drugs produced by eight drug 
manufacturers28, 29  TIRF medicines include fentanyl sublingual and buccal tablets; 
.
lozenges; nasal sprays; and buccal-soluble film. 
Because TIRF drugs have such high risk, the TIRF REMS is designed to be restrictive.  
Some of its requirements are as follows:  
  Prescribers and pharmacists must become certified by taking training every 2  
years and enrolling with the REMS program.  
  Representative samples of prescribers and pharmacists must take a knowledge 
survey for each assessment. 
  Only specially certified pharmacies can dispense TIRF drugs.  
  TIRF drugs can be dispensed for outpatient use only with evidence of safe-use 
conditions.  
  Patients must complete a Prescriber-Patient Agreement Form that states they 
understand the risks of TIRF drugs.  Patients must renew these forms every  2  
years.  
The TIRF drug manufacturers submit REMS assessments to FDA at 6 months and 12 
months after the initial approval date of the REMS, and annually thereafter.  FDAs 
goal is to review each assessment within 6 months of receiving it and provide 
feedback to the drug manufacturers.  Each assessment includes updates on the 
implementation of the various REMS elements or analyses based on data from the 
period of the assessment.  See Appendix A for a detailed list of the TIRF REMS 
requirements, by  assessment period.    
 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Background | 4   Extended release/long-acting opioid drugs  
ER/LA opioids are powerful analgesic medications approved to treat pain severe 
enough to require daily,  around-the-clock, long-term opioid treatment and for which 
alternative treatment options are inadequate.  FDA approved the shared system REMS  
for ER/LA opioids in 2012.  Initially, it applied to 16 drugs produced by 8 drug 
manufacturers.  As of 2017, it covered 67 brand-name and generic drugs produced by 
33 drug manufacturers.30   The most prescribed ER/LA opioids are oxycodone, 
morphine, fentanyl, and methadone.31  
 
Goal of the REMS for ER/LA opioids  
The goal of the REMS for ER/LA opioids is to reduce serious adverse 
outcomes resulting from inappropriate prescribing, misuse, and abuse of 
these medications while maintaining patient access to pain medications.  
Adverse outcomes of concern include addiction, unintentional overdose, and 
death.   
Source:  FDAs review of manufacturers 6-month assessment report for the REMS for ER/LA opioids, 2013.  
 
The main component of the ER/LA REMS  was a voluntary education program for 
prescribers.  The REMS required drug manufacturers to make education programs 
available to prescribers of ER/LA opioids.  The drug manufacturers met this 
requirement by providing grants to accredited continuing education organizations.  
These organizations designed and administered the educational materials based on 
core educational messages provided by FDA.32  Each annual assessment had a 
training target for the number of prescribers who should be trained by  certain time 
intervals after training became available:  
  2 years: 80,000 prescribers  
  3 years: 160,000 prescribers 
  4 years: 192,000 prescribers.33     
The additional components of the REMS for ER/LA opioids include:  
  a medication guide that is dispensed with each prescription;34   
  a timetable for the drug manufacturers to submit assessments;  
  a patient counseling document for prescribers to assist them in properly 
counseling patients;  
  letters to prescribers informing them of the existence of the REMS and 
educational activities; and 
  a website and call center with information that prescribers can use to aid in 
counseling patients on the risks and benefits of ER/LA opioids.35  
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Background | 5   As with the TIRF REMS, manufacturers of ER/LA opioids submit REMS assessments to 
FDA at 6 months and 12  months after the initial approval date of the REMS, and 
annually thereafter.  Each assessment includes updates on the implementation of the 
different REMS elements or analyses based on data from the assessment period.  See 
Appendix A for a detailed list of requirements of the REMS for ER/LA opioids, by 
assessment period.  
Previous OIG work  
This work contributes to the Office of Inspector Generals body of work on opioids by 
shedding light on the role that REMS have played in addressing the opioid epidemic.  
A 2013 OEI report on FDAs REMS program raised concerns about FDAs process for 
reviewing REMS  and the overall effectiveness of the program.36  Specifically, the 
report found that for the REMS we reviewed, (1) half of the assessments that drug 
manufacturers submitted were incomplete, (2) less than 15 percent of REMS had met 
their goals, (3) FDA had not identified reliable methods to assess the effectiveness of 
REMS, and (4) FDAs review teams for manufacturers assessments exceeded its goal 
of 60 days for almost all assessments.   
The OIG report made seven recommendations based on its findings.  The three 
recommendations that remain unimplemented are those for FDA to (1) identify REMS 
that are not meeting their goals and take appropriate actions to protect the public 
health, (2) seek legislative authority to enforce  FDA assessment plans, and (3) ensure 
that assessment reviews are timely.37  
Methodology  
Scope  
We limited our study to the shared system REMS for ER/LA opioids and TIRF drugs 
from their approval by  FDA (2012 and 2011, respectively) through 2017.   We based 
the study on reviews of drug manufacturer assessments submitted to FDA and related 
documents from that period, and interviews  with relevant FDA officials.  
Document review  
We analyzed all documentation for the REMS for ER/LA opioids and TIRF drugs, 
including the following: the 6-, 12-, 24-, 36-, 48-, and 60-month assessments 
submitted by drug manufacturers through 2017; FDA reviews of these manufacturers 
assessments; inspection reports; and other analyses and correspondence.  Both REMS  
have continued to be in effect during the period of our analysis.  
We analyzed the documents for the two REMS to identify several elements, including 
the extent to which:  
  drug manufacturers submitted their assessments on time; 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Background | 6     drug manufacturers assessments were complete;  
  FDA submitted its reviews of those assessments on time; 
  FDA identified deficiencies or requested modifications; and  
  the REMS for ER/LA opioids and for TIRF drugs were meeting their respective 
goals.  
Interviews  
We conducted structured interviews with FDA staff.  We asked them questions about 
FDA oversight of the REMS for ER/LA opioids and for TIRF drugs and about the 
challenges they face.  We also asked FDA about its policies and procedures related to 
REMS oversight and updates on implementing recommendations from the 2013 OIG 
report.    
Standards  
We conducted this study in accordance  with the Quality Standards for Inspection and 
Evaluation issued by the Council of the Inspectors General on Integrity and Efficiency.   
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Background | 7    
FINDINGS  
 
FDAs reviews raised questions about the effectiveness of the 
REMS for TIRF drugs, but data quality affected timely oversight  
After FDA approved the REMS for TIRF drugs in 2011, TIRF manufacturers spent the 
first 2 years getting their REMS established.  FDA found the assessments that drug 
manufacturers submitted during this time to be timely and complete.   
Starting with the 24-month assessment and continuing through the 60-month 
assessment, FDA found data in the assessments suggesting that the manufacturers 
were not meeting all their goals.  FDA also found the data for some of the REMS goals 
to be inadequate.  Given FDAs deliberate approach to decision-making that relies on 
scientifically robust data, FDA consistently responded to its concerns about the data 
by requesting better data from the TIRF drug manufacturers or conducting its own 
analysis.     
In March 2019 FDA announced a modification to the TIRF REMS.  This modification 
included new goals and processes aimed at better ensuring safer, more appropriate 
prescribing of TIRF drugs.    
FDA reviews raised questions about the TIRF REMSs ability to 
measure and meet its goal to mitigate the risk of misuse and 
abuse 
GoalREMS for TIRF Drugs
Starting with the 36-month assessment, FDA 
Mitigate the risk of misuse, abuse, 
struggled to determine from the data that 
addiction, overdose, and serious 
TIRF manufacturers submitted how well they 
complications due to medication 
were meeting the TIRF REMS overarching 
errors by: 
goal and subgoals.  For example, FDA found  Subgoals 
in its reviews of the 36-month and  Prescribing and dispensing TIRF 
48-month assessments that it could not  medicines only to appropriate 
determine whether manufacturers were  patients, which includes use only in 
opioid-tolerant patients. 
meeting the TIRF REMS overarching goal.  
Preventing inappropriate conversion  
(FDA did not directly address the 
between TIRF medicines.  
overarching goal in its review of 
Preventing accidental exposure to 
manufacturers 24-month assessment.)  FDA 
children and others for whom TIRF  
also found that it could not determine from 
medicines were not prescribed.  
the assessments at the 24-, 36-, 48-, and 
Educating prescribers, pharmacists, 
60-month pointsassessments that  and patients on the potential for 
manufacturers submitted from 2013 to the  misuse, abuse, addiction, and 
end of 2016whether manufacturers had  overdose of TIRF medicines. 
met many of the TIRF REMS subgoals.  In  
five instances, FDA determined that two of the subgoals had not been met or had 
FDAs Risk Evaluation and Mitigation Strategies for Opioids: Uncertain Effectiveness in Addressing the Opioid Crisis  
OEI-01-17-00510   Findings | 8   been only partially met.  In its review of the 60-month assessment, FDA determined 
that manufacturers had not met the REMS overarching goal.  See Exhibit 1.   
Exhibit 1:  After its 24-month assessment review, FDA was increasingly 
unable to determine whether manufacturers met the overarching goal and 
subgoals of the TIRF REMS  
 
Source:  OIG analysis of FDA documents. 
Note: FDA did not directly address the overarching goal in its review  of the assessment that manufacturers submitted 
at the 24-month point of the REMS.  
FDAs Risk Evaluation and Mitigation Strategies for Opioids: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Findings | 9   FDA  worked with manufacturers to get better data and  analysis 
from 2014 through 2017  
FDAs reviews of the 24-, 36-, 48-, and 60-month assessments consistently raised 
concerns about some of  the data that manufacturers had submitted, which  
sometimes made it difficult for FDA to determine whether manufacturers were 
meeting the REMS overarching goal and subgoals.  In an effort to obtain high-quality  
data to support its decision making, FDA requested additional data and analysis from 
drug manufacturers after each review, starting with its review of the 24-month 
assessment, which it completed in 2014.   
FDA noted that drug manufacturers data in the 24-month assessment were 
24-month assessment  
disorganized and did not directly measure the goals of the TIRF REMS.  In  particular, 
  Disorganized 
data   FDA noted that the data were inadequate to address the goals related to 
  Data that did not   inappropriate conversions and opioid tolerance.  FDA found adverse-event data to be 
directly address 
problematic,  as those data lacked clinical details including information about 
the goals  
inappropriate conversions, opioid tolerance, and patient outcomes.  Additionally, FDA 
 
found the dispensing data that drug manufacturers submitted to address the subgoal 
Submitted:   
December 2013   of preventing inappropriate conversions between TIRF drugsconversions that could 
Review Completed:   lead to an increased risk of fatal overdosesdid not directly measure outcomes for 
June 2014  
this subgoal (e.g., by using claims data to show that physicians who converted their 
patients from one TIRF drug to another did so correctly).  Rather, the TIRF 
manufacturers submitted survey data that measured prescribers awareness of the 
dangers of inappropriate conversions between TIRF drugs.  
Furthermore, FDAs review found that survey data included within the assessment 
raised questions about whether the REMS  was meeting the fourth subgoal, related to 
educating prescribers and pharmacists.  The data that manufacturers submitted 
showed that only  59 percent of prescribers and 47 percent of pharmacists surveyed 
knew the correct medical indication for TIRF drugs (breakthrough cancer pain).38  In  
both instances, the FDA reviewer was uncertain as to whether prescribers were 
unaware of the approved indication for TIRF drugs, or prescribers knew the approved 
indication and disregarded it.  
(cid:190) In response to these concerns, FDA asked for more and better data in its 
review of the 24-month assessment.  For example, FDA asked for additional 
adverse-event data (including details of how the data were collected) and for 
questions to be added to the surveys.   
For the 36-month assessment, which FDA received in late 2014, FDA once  again 
36-month assessment 
  Data that did not    determined the data to be inadequate with regard to the same three subgoals (i.e., 
directly address  those related to opioid tolerance, inappropriate conversions, and adverse events).   
the goals  
  FDA noted that the manufacturers submitted adverse events reports as evidence 
Submitted:    related to the subgoals regarding prescribing only to opioid-tolerant patients and 
December 2014  
avoiding inappropriate conversions between TIRF drugs.  However, these reports do 
Review Completed:  
not capture information about patients opioid tolerance or inappropriate conversions 
July 2014  
between TIRF drugs.  These reports, as well as FDAs own analysis, left FDA unable to 
FDAs Risk Evaluation and Mitigation Strategies for Opioids: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Findings | 10   determine whether the TIRF REMS  was meeting its overall goal of mitigating the risk 
of misuse and abuse that can lead to addiction, overdose, and serious complications 
due to medication errors.39  
(cid:190) In response, FDA requested better data from drug manufacturers when it 
completed its review.  For example, FDA provided drug manufacturers with 
explicit instructions on how to conduct analyses to determine whether only 
opioid-tolerant patients were being prescribed TIRF drugs and to identify 
inappropriate conversions between TIRF drugs.  
 
In December 2015, the 48-month assessment that manufacturers submitted 
48-month assessment  
  Lack of prescriber  continued to raise FDAs concerns that the subgoals related to opioid tolerance, 
knowledge of   inappropriate conversion, and preventing adverse events were not being met.   
appropriate  
prescribing  FDA remained concerned about the quality of data on prescribing only to opioid-
  tolerant patients.  In response, it asked manufacturers for better data, and they 
Submitted:   
submitted patient summary data that were aggregated.  Those data suggested that 
December 2015  
42 percent of patients were not opioid-tolerant when they  were first prescribed a TIRF 
Review Completed:  
drug, potentially exposing these patients to an increased risk of life-threatening 
June 2016  
respiratory depression.  An FDA reviewer shared these concerns with the 
manufacturers and wrote: [T]his finding is  concerning and the [drug manufacturers] 
should investigate and implement a process to ensure that TIRF prescribers are aware 
of the need for their patients to be opioid-tolerant.39  
Similarly, FDA again raised concerns about the subgoal related to inappropriate 
conversion between TIRF drugs.  Incomplete data in the assessment showed that 
about 17 percent of patients had been switched by their prescribers from one 
regimen of TIRF drugs to another.  Among those 17 percent of patients, about one-
fifth were switched to yet another regimen of TIRF drugs.  However, these data 
submitted by the drug manufacturers did not measure whether these conversions 
between TIRF drugs were inappropriate.  FDA called for further study by the  
manufacturers.  
Finally, FDA found that the manufacturer data on adverse events raised concerns 
about off-label prescribing of TIRF drugs.  Those data showed that among the 291  
deaths associated with TIRF drugs, as many as 57 percent may have involved off-label 
use.40  The prescriber survey data demonstrated that some prescribers believed that 
chronic noncancer pain was an appropriate indication for prescribing TIRF drugs.  
These prescribers stated that they  were prescribing TIRF drugs for back pain, 
neuropathic pain, and post-operative pain.  Their motivation for prescribing TIRF 
drugs off-label included the failure of other drugs, as well as TIRF drugs efficacy  and 
fast-acting nature.  
(cid:190) In response to these findings, FDA requested that the drug manufacturers 
conduct additional analysis on opioid toleranceto include (for comparison 
purposes) analysis on opioid tolerance before and after the 2011 
establishment of the REMSas well as  analysis on inappropriate conversions.  
FDAs Risk Evaluation and Mitigation Strategies for Opioids: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Findings | 11   FDA also requested a meeting to discuss prescribers low awareness of the 
appropriate medical indications for prescribing TIRF drugs.   
The 60-month assessment again caused FDA concern regarding opioid tolerance, 
60-month assessment 
  Concerning data  adverse events, off-label prescribing, and provider education.  For example, FDA 
on opioid  found that the assessment contained concerning data regarding opioid tolerance.  
tolerance  
The drug manufacturers data showed that 35 to 55 percent of patients who were 
  FDAs analysis  
prescribed a TIRF drug were not opioid-tolerant.41  Non-opioid-tolerant patients who 
suggests an 
use TIRF drugs are at an increased risk of life-threatening respiratory depression.   
increase in  
adverse events  
FDA also found that the 60-month assessment included inadequate data, specifically  
over time  
  on adverse events.  In response, FDA conducted its own analysis of adverse events 
Submitted:    and off-label use covering the previous 20 years, which raised further questions about 
December 2016  
the REMS effectiveness and data quality.42  FDA found that the number of adverse 
Review Completed:  
event cases suggesting off-label use increased after 2011.  FDA also noted that rates 
December 2017  
of abuse adjusted for prescribing level increased after the REMS  was established.  FDA 
wrote: [T]he current presentation of the data suggests that, despite the presence of a 
REMS, we observed an increasing trend in prescription-adjusted rates of abuse and 
other significant outcomes for TIRFs over the time period.43, 44    
In addition, the data in the assessment raised questions about the effectiveness of the 
educational efforts.  FDA determined that manufacturers had only partially  met the 
TIRF REMS subgoal of educating prescribers, pharmacists, and patients on TIRF risks.  
TIRF prescribers and pharmacists who were enrolled in REMSand thus had received 
training on the appropriate prescribing of TIRF drugs and their risksfailed to 
correctly  answer questions in a survey  about key  risk messages.  For example, 
23 percent of prescribers incorrectly responded that patients could continue to take 
TIRF medicines even after discontinuing around-the-clock use of opioids.  The TIRF 
REMS training states that patients who do this are at an increased risk of death.  Like 
prescribers, the surveyed patients and pharmacists also consistently failed to answer 
questions correctly.  See Appendix B for the results of the knowledge survey goals 
required by the REMS for TIRF drugs that failed to meet performance goals.  
(cid:190) In response to these findings, FDA requested that the drug manufacturers 
conduct additional analysis on opioid tolerance.  It also requested that the 
drug manufacturers submit adverse-event data broken out by each TIRF drug.  
FDA held a public  advisory committee meeting about the TIRF REMS in 2018.  
FDA  modified the goals of the TIRF REMS in 2019 to improve 
processes for appropriate  prescribing  
In August 2018, FDA held a public advisory  committee meeting to discuss results from 
FDA required 
the manufacturers assessments of the TIRF REMS and possible modifications to the 
modification, March  
structure of the TIRF REMS.  A group of researchers submitted comments to the 
2019 
advisory  committee that also questioned the efficacy of the TIRF REMS and 
contended that FDA had years of evidence pointing to inappropriate prescribing and 
limited oversight.45  
FDAs Risk Evaluation and Mitigation Strategies for Opioids: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Findings | 12   The advisory  committee meeting included recommendations that would lead to a 
modification to the TIRF REMS.  The advisory  committee recommended that no 
further study of inappropriate conversions was needed as the data suggested that 
dosing conversions between TIRF medicines occurred infrequently, and that 
conversion guidance for prescribers is available in labeling and other online sources.46   
In the same meeting, FDA clarified that the TIRF REMS was not necessarily  intended to 
restrict off-label prescribing, but rather to ensure patients who were prescribed the 
drug were opioid-tolerant.47   
In March 2019 FDA announced a modification to the TIRF REMS.  This modification 
included new goals and processes.  The new goals place a greater emphasis on 
ensuring that patients who are prescribed TIRF drugs are opioid-tolerant.  New  
processes include requiring documentation that patients are opioid-tolerant and 
creating a patient registry to better monitor adverse events, including accidental 
exposure, misuse, abuse, addiction, and overdose.  In a letter to manufacturers of TIRF  
drugs, FDA  cited the inadequacy of available data submitted by manufacturers in 
assessment reports as the reason for creating the patient registry.   
 
Goals of the REMS for TIRF drugs (submitted by drug manufacturers in 2019; 
currently under FDA review)  
1.  Mitigate the risk of overdose by: 
a)  Requiring  documentation of opioid tolerance with  every TIRF 
prescription for outpatient use.   
b)  Requiring inpatient pharmacies to verify opioid tolerance in inpatients 
who require TIRF medicines while hospitalized.  
c)  Educating prescribers, pharmacists, and patients that the safe use of 
TIRF medicines requires patients to be opioid-tolerant throughout  
treatment.   
2.  Mitigate the risk of accidental exposure by educating health care providers (HCPs) 
and patients about proper storage and disposal of TIRF medicines. 
3.  Assess safe use and trends in accidental exposure, misuse, abuse, addiction,  and 
overdose by enrolling all patients who receive a TIRF medicine for outpatient 
 use in a registry.  
Source:  FDAs REMS modification letter to manufacturers of TIRF drugs, 2019.  
 
The modifications hold some promise for enhancing the TIRF REMS, but they may not 
fully address all the shortcomings that FDA identified.  For example, the addition of a 
registry will likely lead to better data on adverse events.  However, the proposed goals 
no longer say that TIRF drugs should be prescribed and dispensed only to 
appropriate patients (i.e., patients with breakthrough cancer pain), which may signal 
to prescribers that prescribing TIRF drugs off-label to treat patients with wide-ranging 
pain symptoms (i.e., low-level chronic pain, post-operative acute pain, etc.) is 
appropriate.  Off-label prescribing is legal, but can be abused, as it has been with TIRF 
FDAs Risk Evaluation and Mitigation Strategies for Opioids: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Findings | 13   drugs in the past.  Lastly, the new goals do not directly address inappropriate 
conversions.   
The prescribing of these medicines for non-FDA approved uses to non-opioid-
tolerant patients tells us that there may be a disconnect between prescriber 
knowledge and prescriber behavior.... While all opioids pose serious risks, these are 
not your  typical opioids and should be prescribed by providers with extra care and 
attention.  
Former FDA Commissioner Scott Gottlieb, M.D.   
Source:  Statement by then-Commissioner Scott Gottlieb, March 27, 2019.  
After being unable to determine whether the REMS for ER/LA 
opioids reduced adverse outcomes, FDA modified the REMS 
goal to focus instead on education 
In 2012, the year after FDA approved the TIRF REMS, FDA approved the REMS for 
ER/LA opioids.  ER/LA opioids are powerful analgesic medications approved to treat 
pain severe enough to require daily, around-the-clock, long-term opioid treatment.  
ER/LA opioids are addictive and are more commonly prescribed than TIRF drugs.  
The manufacturers of ER/LA opioids spent the first 2 years getting their REMS 
established.  FDA found the assessments that drug manufacturers submitted during 
this time (at 6 and 12 months) to be timely and complete.  The goal of the REMS for 
ER/LA opioids was to reduce serious adverse outcomes.  While baseline data on 
adverse outcomes caused by ER/LA opioids was available, FDA found that it was not 
possible to attribute any  changes in adverse outcomes directly to the REMS efforts.  A 
peer-reviewed research article published in December 2019 cited similar findings.48   
Furthermore, FDA questioned manufacturer-submitted data on ER/LA opioids, but its 
late reviews limited the effectiveness of its oversight and delayed its eventual 
modification of the REMS.   
FDA could not determine whether the REMS for ER/LA  opioids 
was  meeting its  overarching goal  of 
reducing serious adverse outcomes, but 
Goal of the REMS for 
the agency found that manufacturers 
ER/LA Opioids 
did not meet targets for training  Reduce serious adverse  
outcomes resulting from 
prescribers  
inappropriate prescribing, 
misuse, and abuse of ER/LA 
Starting with the 24-month assessment in 2014, FDA 
opioid analgesics, while 
reviewers were skeptical of ER/LA opioid 
maintaining patient access 
manufacturers claims about reducing adverse 
to pain medications  
outcomes.  In an effort to obtain high-quality data to 
FDAs Risk Evaluation and Mitigation Strategies for Opioids: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Findings | 14   support its decision making, FDA stated that it would need more data to confirm 
manufacturers claims about progress.  
Despite having received additional data from manufacturers, FDA remained skeptical 
upon reviewing the 36-month assessment (submitted in 2015).  That was the first 
assessment that included all necessary data to address progress in reducing adverse 
outcomes, and the drug manufacturers reported decreases both in adverse outcomes 
and in prescribing.  However, upon further analysis, FDA found that both had been 
decreasing since before the REMS began,  making it impossible for FDA to attribute 
the decreases to the REMS  with the data provided by drug manufacturers.  As a result, 
FDA was unable to determine whether the manufacturers met the REMS goal in the 
36-month review and all subsequent reviews.49  See Exhibit 2.  
 
Exhibit 2: FDA was unable to determine whether manufacturers met the 
overarching goal of the REMS for ER/LA opioids 
 
Source:  OIG analysis of FDA documents  
 
In addition, FDA found that manufacturers of  ER/LA opioids failed to meet training 
targets.  For the three assessment periods in which the manufacturers were required 
to report the number of  prescribers trained on safe prescribing habits for opioids, 
manufacturers failed to achieve even half their annual training targets.  They noted 
that it was considerably  more challenging than expected to get prescribers to take the 
training, because many other sources for training related to opioids became available.  
Prescribers could not distinguish between training associated with REMS.  See Exhibit 
3.  
 
 
 
 
FDAs Risk Evaluation and Mitigation Strategies for Opioids: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Findings | 15   Exhibit 3:  Manufacturers of ER/LA opioids failed to achieve even half of the 
REMS targets for training prescribers  
Target  Actual   Percentage of  
Assessment 
number   number   target 
36-month    80,000   37,512   47%  
48-month  160,000   66,881   42%  
60-month  192,000   88,316   46%  
Source:  OIG analysis of FDA documents  
FDAs late reviews of the assessments from manufacturers of 
ER/LA opioids  limited the effectiveness of its oversight  
From 2015 through 2018, FDA was late in completing its reviews of assessments from  
manufacturers of ER/LA opioids (see Appendix C).  In 2015, FDA took just 1 month 
beyond its goal of 6 months to complete the review, but by 2016, FDA was late by 6 
months.  That means that after receiving the 36-month assessment from 
manufacturers of ER/LA opioids, FDA took more than a year to request, in July 2016, 
that the manufacturers find other data sources and conduct new analyses to properly 
assess whether the REMS had contributed to the decreases in adverse outcomes and 
prescribing.  Five weeks later, in September 2016, manufacturers submitted their 
48-month assessment.  This assessment contained data and analysis methods that 
mirrored what manufacturers had submitted in the 36-month assessment.  FDA had 
determined those methods to be inadequate, but 5 weeks was not enough time for 
manufacturers of ER/LA opioids to revise their approach.   
FDA continued to be late in its reviews of manufacturers assessments, further 
disrupting the intended cycle.  In June 2017, when FDA received the 60-month 
assessment from manufacturers, it had not yet completed its review of the 48-month 
assessment.  FDA informed the drug manufacturers that it would withhold comments 
on the 48-month assessment and submit them along with its comments on the 60-
month assessment.  FDA was 2 months late in submitting its review of manufacturers 
60-month assessment (together with its comments on the 48-month assessment).  
As a result, manufacturers of ER/LA opioids were unable to address the deficiencies 
that FDA identified in the 48-month assessment until they submitted the 72-month 
assessment.   
In 2018, FDA modified the REMS to make the overarching goal 
more measurable  by focusing  on education rather than outcomes  
FDA required  Shortly after the 72-month assessment period, and after 4  years of questioning drug 
modification:    
manufacturers ability to measure the REMSs success in reducing prescribing rates 
September 2018  
and serious adverse outcomes, FDA modified the REMS for ER/LA opioids.  In 2018, 
FDAs Risk Evaluation and Mitigation Strategies for Opioids: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Findings | 16   FDA completely  changed the goal and also modified the REMS to include not just 
ER/LA opioids, but also immediate-release opioids.  Accordingly, FDA changed the 
name of the REMS, making it the REMS  for Opioid Analgesics.   
The REMS new goal no longer focuses 
Goals of the REMS for  opioid 
on outcomes; instead, it changes the 
analgesics (effective 2018)  
focus to education for prescribers and 
To educate prescribers and other healthcare 
healthcare providers.  Although 
providers (including pharmacists and nurses) 
education is measurable, it does not 
on the treatment and monitoring of patients 
necessarily follow that prescriber and 
with pain by:  
healthcare provider education 
1.  Ensuring that training is effective in 
mitigates the risk of opioid misuse and 
educating prescribers and other 
abuse.  Rather, the goal now focuses  health care providers, and  
on prescribers and other healthcare  2.  Informing patients about their roles 
providers being trained on the  and responsibilities regarding their 
fundamental concepts of pain  pain treatment plan  
management and how to counsel 
patients about the safe use of opioids.  During a 2016 advisory  committee meeting, 
FDA sought feedback from committee members on the issue of mandatory training 
for prescribers.  Most advisory  committee members recommended that training be 
required.50  FDA decidedciting potential impact  on appropriate patient access and 
burden to the health care delivery systemthat the modified REMS  would not require 
prescribers to take the training; training remains voluntary.   
FDA faces challenges to ensuring that REMS mitigate opioid 
misuse and abuse 
While the severity of the opioid crisis became more apparent over time and the 
Federal Government and States launched initiatives to combat opioid abuse, FDA was 
struggling to measure the effectiveness of the REMS for TIRF drugs and the REMS for 
ER/LA opioids in mitigating the misuse of opioids.  According to FDA, the following 
factors have contributed to the agencys struggles to ensure that the two REMS meet 
their goals:  difficulty in measuring progress, the mandate to minimize the extent to 
which REMS  creates a burden to the health care system, and limited enforcement 
authority.    
Because of measurement challenges, FDA struggled to determine 
the extent to which REMS were effective 
FDA faces measurement challenges in addition to the limitations in the data from the 
drug manufacturers.  For example, the lack of baseline data, such  as that on 
preventing inappropriate conversions between TIRF medications, hampers meaningful 
comparisons.  FDA also stated that surveillance data are limited because no single, 
reliable national databases exist that capture all adverse events.  Additionally, no 
good linkages exist across the existing surveillance databases.  
FDAs Risk Evaluation and Mitigation Strategies for Opioids: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Findings | 17   Further complicating FDAs ability to determine whether REMS are effective are the 
various other efforts underway to address the opioid epidemic.  These efforts include 
(among others) new standards for prescribing opioids and increased use of 
prescription drug monitoring programs.  These additional efforts have made it 
difficult to determine whether REMS are having a positive impact or other 
interventions are responsible for the outcomes.  The array of initiatives addressing 
opioid misuse and abuse make it difficult to distinguish the individual effects of the 
REMS.   
Finally, although FDA told us that opioid manufacturers had made a good-faith effort 
to meet the requirements of the REMS, some manufacturers engaged in deceptive 
marketing tactics.  For example, recent State court settlements have held opioid drug 
manufacturers accountable for damages resulting from deceptive opioid marketing 
that started in the mid-1990s.51  Such deceptive marketing practices may undermine 
the educational messages of the REMS training and the overall effectiveness of the 
two REMS.  
Shared system REMS help reduce burden but may  mask 
problems with individual drugs or product categories  
Shared system REMS  aid efficiency  and lessen the burden on individual 
manufacturers, prescribers, and pharmacies.  Indeed, the Food and Drug 
Administration Amendments Act, which provided FDA with the authority to require 
REMS, calls on FDA to minimize the burden of REMS on the health care system and 
patients.   
However, a shared system REMS can also lead to less precise analysis.  In the aim of 
reducing burden, shared system REMS aggregate data across drugs and product 
categories.  When needed to further explore a potential problem or safety  concern, 
FDA has requested product-specific data from manufacturers to support its analysis.  
For example, when FDA conducted its review of TIRF drug manufacturers 48-month 
assessment, it began to get a clearer picture of how TIRF drugs were prescribed off-
label.  When FDA reviewed the 60-month assessment, it more clearly established that 
this was the case but was still unable to determine whether the problem was caused 
by one specific TIRF product.  After this review, FDA had to request that the drug 
manufacturers submit product-specific reports in their 72-month assessment.   
FDA has limited enforcement authority associated with REMS; it 
did not exercise that authority for the opioid REMS    
For a manufacturer that violates an approved REMS, FDA can exercise its authority 
and regulatory discretion to, among other things, deem a drug misbranded or impose 
civil monetary penalties.52, 53  As of September 2019, FDA had not determined that 
there were violations of either of the two shared system REMS.  FDA told us that 
sometimes a REMS may  not be meeting its goals because of unforeseen 
FDAs Risk Evaluation and Mitigation Strategies for Opioids: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Findings | 18   circumstances and through no fault of a manufacturer.  Under those circumstances, 
FDA would generally modify a REMS.  
   
FDAs Risk Evaluation and Mitigation Strategies for Opioids: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Findings | 19   CONCLUSION / RECOMMENDATIONS 
 
 
With nearly  47,000 overdose deaths in 2018, the opioid crisis continues to be a 
serious public health emergency and has an associated economic burden that is 
estimated at $78 billion annually.   Most overdose deaths have been caused by  
illegally sourced fentanyl, but people who abuse opioids are often introduced to 
opioids via prescriptions for legal opioids.  Although opioid prescribing has been 
decreasing since 2012, opioids are still heavily prescribed.  
FDA has taken many steps to address the opioid crisis, such as expanding access to 
naloxone and promoting access to medication-assisted treatment for opioid 
addiction.  Among those steps, FDA has also used REMS.   
Based on our review, it appears that REMS are not well-suited to quickly address the 
opioid crisis.  The REMS  for TIRF and ER/LA opioids both rely largely on prescriber 
education to change prescribing habits.  This takes time to have an impact and can be 
countered by pharmaceutical marketing campaigns designed to increase prescribing.  
In addition, FDAs deliberate approach to decision-makingwhich is central to its 
mission to protect the publics healthrelies on scientifically robust, accurate data, 
which focused FDAs attention, for years, on improving the serious data-quality issues 
in the manufacturer-submitted assessments.  
By  2019,  FDA modified both REMS.  The updated goals for the REMS for TIRF drugs 
hold some promise.  The more prescriptive goals focus on areas of high concern such 
as prescribing only to opioid-tolerant patients and establish requirements to gather 
better data to better monitor adverse events, including accidental exposure, misuse, 
abuse, addiction, and overdose.  However, the new goals omit references to 
appropriate prescribing and inappropriate conversions, which are also  of concern.  In  
addition, although the changes to the REMS  for ER/LA opioids (which has been 
broadened and is now the REMS for opioid analgesics) include a new goal that 
focuses on education and training, FDA made that training voluntary rather than 
requiring that providers take the REMS training, in part because of its concerns about 
burden on drug manufacturers, prescribers, and pharmacies.  
We recommend that FDA:  
Use the new TIRF REMS patient registry to monitor for known 
areas of risk, such as inappropriate conversions and off-label 
prescribing  
The previous goals for the TIRF REMS specifically addressed inappropriate 
conversions.  FDAs review of multiple TIRF assessments demonstrated that this was 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis  
OEI-01-17-00510   Conclusion | 20   an area of risk and concern.  However, FDAs modification of the TIRF REMS  
eliminated this goal.  According to FDA, the data suggested that dosing conversions 
between TIRF medicines occurred infrequently, and that conversion guidance for 
prescribers is available in labeling and other online sources.  However, prescribers do 
not always seek out labeling and other sources for dosing information.  Because of 
the differences among TIRF drugs, prescribers should exercise care when converting 
between TIRF drugsi.e., when switching a patient from one TIRF drug to another
or the patient may have an increased risk of a fatal overdose.  Given that the new  
patient registry  will make data more readily available, FDA should monitor the data 
for inappropriate conversions.  
The new proposed goals for the TIRF REMS also no longer state that TIRF drugs 
should be prescribed and dispensed only to appropriate patients.  Supporting this 
decision, FDA stated that the REMS for TIRF drugs was not intended to prevent off-
label prescribing, but rather to ensure that patients who were prescribed the drug 
were opioid-tolerant.  
We appreciate that FDA does not want to interfere with the prescribing habits of 
physicians and that off-label prescribing is generally legal; however, using TIRF drugs 
for a purpose other than for which they were clinically tested and approved could 
have serious health consequences.  Furthermore, off-label prescribing has been a 
known area of risk for TIRF drugs.  In  May 2019, a Federal jury found executives from 
the pharmaceutical company that makes Subsys (a TIRF medicine included in the 
REMS) guilty of bribing medical practitioners to prescribe Subsys  off-label.54  FDA 
approved TIRF drugs for the management of breakthrough pain in adult cancer 
patients who are already  tolerant to around-the-clock  opioid therapy for their 
underlying, persistent cancer pain.  TIRF drugs are 50 to 100 times more powerful 
than morphine and can cause life-threatening respiratory depression in patients who 
are not opioid-tolerant.  
Given the risk, monitoring off-label prescribing could flag safety issues.  Concerning 
patterns of off-label prescribing could be flagged for further review regarding clinical 
safety  or referred to enforcement agencies for possible violations of off-label 
marketing by manufacturers.   
Strengthen the REMS for opioid analgesics (the successor to 
ER/LA opioids) by requiring prescriber training 
FDA should take advantage of its existing authorities and require prescriber training 
for the REMS  for opioid analgesics rather than leaving it voluntary.  Although 
changing prescriber behavior through education certainly has it limits, as this report 
acknowledges, taking strong steps to ensuring that prescribers have the expertise to 
appropriately prescribe opioids is critical.  Prescribers are the clinical gatekeepers for 
drugs that have harmed patients and communities across the country.  Furthermore, 
during a 2016 advisory  committee meeting, most of the advisory committee members 
recommended that training be required.  There are a number of ways that FDA could 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Conclusion | 21   do this while working to minimize burden on providers.  For example, according to 
FDA, most, but not all, States currently require some opioid-related education for 
physicians State licensure.  FDA could allow this training, if the content meets FDA 
approval, to meet some or all of the mandated prescriber training needed for the 
REMS.   
Enhance its REMS assessment review process 
FDA should take additional steps to enhance its review of the REMS assessments 
submitted by manufacturers for the REMS for TIRF and opioid analgesics.  First, FDA 
should strive to meet its REMS review goal of 6 months.  We recognize the challenges 
inherent in balancing FDAs reliance on careful analysis with the importance of  
providing timely feedback to manufacturers.  However, fighting the opioid epidemic is 
a top HHS priority  and, in response to the urgent need to continue to combat the 
opioid crisis, FDA should strive to do more to ensure its reviews are completed in time 
for manufacturers to be able to respond to the feedback in the next assessment.  
Second, FDA should seek to include a wide range of information to fully understand 
prescribing patterns and their association with opioid abuse, misuse, and overdoses.  
For example, FDA could include information from FDAs Office of Prescription Drug 
Promotion in its REMS assessment review process.  This office has the potential to 
provide useful information regarding how manufacturers are promoting opioids and 
inappropriate opioid prescribing trends.  
Seek additional authority to ensure that manufacturers are held 
accountable when appropriate  
FDA can exercise its authority and regulatory discretion to, among other things, deem 
a drug misbranded or impose civil monetary penalties on manufacturers that violate 
approved REMS.  However, these measures are not necessarily practical for simple 
violations of REMS requirements and could reduce access to appropriately prescribed 
drugs.  FDA should seek additional, more streamlined authority to levy fines against 
companies when they violate their REMS.  One example of a violation might be a 
manufacturer failing to make a good-faith effort to provide data to FDA that are 
readily available.   
 
 
 
 
AGENCY COMMENTS AND OIG RESPONSE 
 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Conclusion | 22   AGENCY COMMENTS AND OIG RESPONSE 
 
FDA concurred with our first recommendation and noted that its 2019 proposed 
modification of the REMS for TIRF drugs would add a patient registry.  This registry 
would enable FDA to better monitor usage in outpatients taking a TIRF medicine with 
respect to opioid tolerance and related serious adverse events including overdose and  
death.  This registry  will capture specific  drug and dosing information for each patient, 
allowing for the monitoring of inappropriate dosing conversions between TIRF 
medicines.  Furthermore, it will also capture information on the type of pain the 
patient is experiencing (e.g., cancer or noncancer pain), which will enable monitoring 
of off-label use.  We look forward to FDA providing an update on its monitoring 
efforts in its Final Management Decision.  
FDA did not concur with our second recommendation and noted that it supports 
education for all opioid prescribers but does not believe that mandating education 
through the REMS  for opioid analgesics (the successor to ER/LA opioids) is a practical 
solution.  FDA stated that such a mandate would require setting up a restrictive 
program, similar to the REMS for TIRF drugs, but on a much larger scale.  FDA noted 
that by raising barriers to health care providers, such a system could restrict patient 
access to the medications.  We acknowledge that establishing a restrictive system for 
the REMS for opioid analgesics could be burdensome and potentially impact patient 
access to these drugs.  However, given that providers are the frontline gatekeepers for 
drugs that contribute to the opioid crisis, it is critical that their clinical decisions be 
informed by the most up-to-date, unbiased science regarding the benefits and risks 
of prescribing opioids.  In the 2016 meeting of the advisory  committee for the REMS 
on ER/LA opioids, committee members echoed this critical need by providing broad 
support for required education.  To reduce the burden and potential for affecting 
patient access to opioids, FDA could try other approaches to requiring training, such 
as by modifying the REMS for opioid analgesics to require that manufacturers 
conduct more aggressive outreach to prescribers regarding training.  FDA could also 
consider working with the States that currently do not require training as a condition 
of physicians State licensure.   
FDA concurred with the third recommendation and highlighted an April 2020 
workgroup established to oversee the REMS Assessment Modernization and 
Improvement Project as a means to improve the efficiency  of its REMS  assessment 
reviews.  This workgroup will also consider whether other offices within FDA, such as 
FDAs Office of Prescription Drug  Promotion, should be regularly consulted as part of 
the REMS assessment review process.  We appreciate FDAs efforts to establish a 
workgroup charged with improving the REMS assessment review process.  We look 
forward to FDA detailing in its Final Management Decision the steps it has taken or 
plans to take to enhance that process, including any role for consulting other offices 
within FDA, as well as any outcomes achieved.  
 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis  
OEI-01-17-00510   Conclusion | 23   Finally, FDA did not explicitly concur with our fourth recommendation.  It noted that it 
will form a  working group to explore the feasibility of legislative language to provide 
more streamlined authority than FDA currently has to levy fines against manufacturers 
when they violate their REMS.  We ask that FDA, in its Final Management Decision, 
specify the status of this working group.  
Appendix D provides the full text of FDAs comments. 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Conclusion | 24    
APPENDIX A 
 
Requirements of the REMS for TIRF drugs and for ER/LA 
opioids, by assessment period  
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis  
OEI-01-17-00510   Appendix A | 25   
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Appendix A | 26    
APPENDIX B 
 
Results of knowledge surveys required by the REMS for TIRF 
drugs failed to  meet performance goals 
 
Source: FDA reviews of data submitted by the TIRF REMS administrator  
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis  
OEI-01-17-00510   Appendix B | 27   
APPENDIX C 
 
Timeline for manufacturer submissions and FDA reviews, July 
2014-Feburary 2018  
 
Manufacturers submitted timely assessments, but FDA was often late with its reviews.*  
 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis  
OEI-01-17-00510   Appendix C | 28    
APPENDIX D 
 
Agency Comments  
 
 
 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis  
OEI-01-17-00510   Appendix D | 29   
 
 
 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Appendix D | 30    
 
 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Appendix D | 31    
 
 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Appendix D | 32    
 
 
 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Appendix D | 33    
 
 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Appendix D | 34   FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Appendix D | 35    
ACKNOWLEDGMENTS AND CONTACT 
 
Acknowledgments  
Chris Galvin served as the team leader for this study, and Malaena Taylor served as 
the lead analyst.  Others in the Office of Evaluation and Inspections who conducted 
the study include Sarah Hijaz.  Office  of Evaluation and Inspections staff who provided 
support include Clarence Arnold, Adam Freeman, Althea Hosein, and Christine Moritz.  
We would also like to acknowledge the contributions of other Office of Inspector 
General staff, including Jessica Swanstrom.   
This report was prepared under the direction of Joyce Greenleaf, Regional Inspector 
General for Evaluation and Inspections in the Boston regional office, and Danielle 
Fletcher, Deputy Regional Inspector General.  
Contact 
To obtain additional information concerning this report, contact the Office  of Public 
Affairs at  Public.Affairs@oig.hhs.gov.  OIG reports and other information can be found 
on the OIG website at oig.hhs.gov.  
Office of Inspector General 
U.S. Department of Health and Human Services 
330 Independence Avenue, SW 
Washington, DC 20201  
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis  
OEI-01-17-00510   Acknowledgments and Contact | 36   
ABOUT THE OFFICE OF INSPECTOR GENERAL  
 
 
The mission of the Office of Inspector General (OIG), as mandated by  Public Law 95-
452, as amended, is to protect the integrity of the Department of Health and Human 
Services (HHS) programs, as well as the health and welfare of beneficiaries served by  
those programs.  This statutory mission is carried out through a nationwide network  
of audits, investigations, and inspections conducted by the following operating 
components:  
The Office of Audit Services (OAS) provides auditing services for HHS, 
either by conducting audits with its own audit resources or by overseeing audit work  
done by others.  Audits examine the performance of HHS programs and/or its 
grantees and contractors in carrying out their respective responsibilities and are 
intended to provide independent assessments of HHS programs and operations.  
These audits help reduce waste, abuse, and mismanagement and promote economy 
and efficiency throughout HHS. 
The Office of Evaluation and Inspections (OEI)  conducts national 
evaluations to provide HHS, Congress, and the public with timely, useful, and reliable 
information on significant issues.  These evaluations focus on preventing fraud, waste, 
or abuse and promoting economy, efficiency, and effectiveness of departmental 
programs.  To promote impact, OEI reports also present practical recommendations 
for improving program operations.  
The Office of Investigations (OI) conducts criminal, civil, and administrative 
investigations of fraud and misconduct related to HHS programs, operations, and 
beneficiaries.  With investigators working in all 50 States and the District of Columbia, 
OI utilizes its resources by actively coordinating with the Department of Justice and 
other Federal, State, and local law enforcement authorities.  The investigative efforts 
of OI often lead to criminal convictions, administrative sanctions, and/or civil 
monetary penalties.  
The Office of Counsel to the Inspector General (OCIG)  provides  
general legal services to OIG, rendering advice and opinions on HHS programs and 
operations and providing all legal support for OIGs internal operations.  OCIG  
represents OIG in all civil and administrative fraud and abuse cases involving HHS 
programs, including False Claims Act, program exclusion, and civil monetary penalty  
cases.  In connection with these cases, OCIG  also negotiates and monitors corporate 
integrity agreements.  OCIG renders advisory opinions, issues compliance  program 
guidance, publishes fraud alerts, and provides other guidance to the health care 
industry concerning the anti-kickback statute and other OIG enforcement authorities. 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis  
OEI-01-17-00510   About OIG | 37   
EEEEEEEEEEEEEEEEEENNNNNNNNNNNNNNNNNNDDDDDDDDDDDDDDDDDDNNNNNNNNNNNNNNNNNNOOOOOOOOOOOOOOOOOOTTTTTTTTTTTTTTTTTTEEEEEEEEEEEEEEEEEESSSSSSSSSSSSSSSSSS                  
1  State of Oklahoma  vs Purdue Pharma, No. CJ-2017-816 (filed August 26, 2019).  Accessed at 
https://nondoc.com/2019/08/26/read-the-full-johnson-johnson-opioid-ruling-from-judge-thad-balkman/ on December 20,  
2019.  
2 National Academies of Sciences, Engineering, and Medicine, Pain Management and the  Opioid Epidemic: Balancing Societal 
and Individual Benefits  and Risks of Prescription Opioid Use, 2017, pp. 1-7 through 1-9.  
3 CDC, Opioid Overdose.  Accessed at  https://www.cdc.gov/drugoverdose/data/prescribing/overview.html on September 8, 
2020.  
4 CDC, Drug Overdose Deaths.  Accessed at https://www.cdc.gov/nchs/data/databriefs/db356_tables-508.pdf#3 on February 5,  
2020.  
5 The Secretary has renewed the declaration of national public health emergency multiple times since 2017.  
6 Florence CS, Zhou C, Luo F, Xu L., The Economic Burden of Prescription Opioid Overdose, Abuse, and Dependence in the 
United States, 2013, Med Care 2016;54(10):901-906.  
7 FDA,  FDA Opioids Action Plan.  Accessed at  https://www.fda.gov/drugs/information-drug-class/fda-opioids-action-plan on  
February 12, 2020.  
8 The Food and Drug Administration Amendments Act, P.L. No. 110-85 (Sept. 27, 2007) added  505-1 to the FD&C Act, which 
allows FDA to require a REMS  at the time of a new drugs approvalif FDA, among other things, becomes aware of new safety 
informationor after a drug has been on the market.  
9 This review will focus on FDA-approved, outpatient, pain-management opioids: ER/LA opioids and TIRF drugs. 
10 Fentanyl is 50 to 100 times stronger than morphine, and an illegal version is often mixed with heroin for sale on the street.   
The number of deaths due to overdoses on fentanyl or other synthetic opioids nearly doubled annually between 2013 and  
2016.  See CDC, Data Brief 294Drug Overdose Deaths in the United States, 1999-2016.  Accessed at: 
https://www.cdc.gov/nchs/data/databriefs/db294_table.pdf#4 on February 2, 2020.  
11 Pharmacies dispensed an average of 93 million opioid prescriptions per year from 1991 to 1999.  In 2018, pharmacies 
dispensed 168 million opioid prescriptions.  See: CDC, Prescription Drug Abuse and Overdose in the United States, 2010.  
Accessed at https://secure.in.gov/attorneygeneral/files/Jones_Indiana_RX_Meeting_-_CJONES(5).pdf on January 3, 2018; and 
CDC, Annual Surveillance Report of Drug-Related Risks and Outcomes, 2018.  Accessed at 
https://www.cdc.gov/drugoverdose/pdf/pubs/2018-cdc-drug-surveillance-report.pdf January 11, 2019.  
12 CDC, U.S. Opioid Prescribing  Rate Maps.  Accessed at  https://www.cdc.gov/drugoverdose/maps/rxrate-maps.html on  
February 12, 2019.  
13 National Academies of Sciences, Engineering, and Medicine,  Pain Management and the  Opioid Epidemic: Balancing Societal 
and Individual Benefits  and Risks of Prescription Opioid Use, 2017, pp. ix, 1-11, and 1-19.   
14 Additional factors may have contributed to the opioid crisis, including pain management trends and socioeconomic factors.  
15 CDC, Drug Overdose Deaths in the  United States, 1999-2017,  2018.  Accessed at  
https://www.cdc.gov/nchs/data/databriefs/db329-h.pdf on February 8 , 2019.  
16 FDA,  Development & Approval Process (Drugs).  Accessed at  
https://www.fda.gov/drugs/developmentapprovalprocess/default.htm on April 18, 2019. 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis  
OEI-01-17-00510   Endnotes | 38 
   
 
17 FD&C Act   505-1(a).      
18 FD&C Act  505-1(e).  In instances where FDA determines elements to assure safe use are required, FD&C Act  505-1(f)(3).  
19 FD&C Act   505-1(f).  REMS may also include, where appropriate, packaging and disposal elements.  See FD&C Act  505-
1(e)(4).  
20 FD&C Act   505-1(f)(5).    
21 FD&C Act   505-1(a) and (h).  
22 FD&C Act   505-1(h).  
23 FDAs draft policy and procedures manual was first completed in mid-2018.  FDA stated that the document largely codified 
the procedures that it had been following since it implemented REMS.  FDA stated its goal is to review assessments is  
6 months, but reviews may take longer depending on their complexity.  
24 FD&C Act  505-1(h)(1)-(2). 
25 FD&C Act   505-1(h)(2).  The Division of Risk Management leads FDAs review of REMS.  Additional divisions potentially  
involved in a REMS Assessment review include the Office of Compliance; Office  of Surveillance and Epidemiology; and Office of 
New Drugs.  See Procedures section from FDAs DRAFT  REMS Assessment MAPP, August 18, 2019, available at: 
https://www.fda.gov/media/133675/download. 
26 Patients considered opioid-tolerant are those who are regularly taking at least: 60 mg oral morphine/day; 25 mg transdermal 
fentanyl/hour; 30 mg oral oxycodone/day; 8 mg oral hydromorphone/day; 25 mg oral oxymorphone/day; or an equianalgesic 
dose of another opioid for 1 week or longer.  
27 See FDA, Approved Risk Evaluation and Mitigation Strategies (REMS)Transmucosal Immediate-Release Fentanyl (TIRF) 
Products, https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=RemsDetails.page&REMS=60.  The TIRF drugs  
Fentora and Actiq were in FDAs RiskMAP program, which was the predecessor program to  REMS.  
28 FDA,  Approved Risk Evaluation and Mitigation Strategies (REMS)Transmucosal Immediate-Release Fentanyl (TIRF) Products, 
https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=RemsDetails.page&REMS=60.   
29 The TIRF REMS structure that this report presents reflects that which was in place for our review and, therefore, our findings.  
See p. 14 for a further discussion of the changes to the TIRF REMS.  
30 The structure of the REMS for  ER/LA opioids that this report presents reflects that which was in place for our review and, 
therefore, our findings.  See p. 18 for a further discussion of the changes to the REMS for ER/LA opioids.  
31 Utilization data taken from the 60-month assessment report for the REMS for ER/LA opioids. 
32 A draft version of the FDA Education Blueprint for Health Care Providers Involved in the Treatment and Monitoring of  
Patients with Pain  (FDA Blueprint) contained the core messages found in the REMS for ER/LA opioids training.  
33 The ER/LA opioids REMS training goal of 320,000 prescribers was based on a 2011 estimate of the number of prescribers 
who had prescribed an ER/LA opioid in the previous year.   
34In accordance with 21 CFR  208.24.  
35 This list of requirements is specifically called Elements to Assure Safe Use (ETASU).  ETASU is one of the four possible  
components of every REMS, with the others being a medication guide, a communication plan, and considerations for safe 
packaging and disposal.  Neither the REMS for ER/LA opioids  nor the REMS for TIRF drugs includes a communication plan, but 
 
 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Endnotes | 39  
   
 
both include all three remaining components.  The Substance Use-Disorder Prevention That Promotes Opioid Recovery and 
Treatment for Patients and Communities Act (2018) codified changes to FD&C Act  505-1(e)(4) to include components related 
to packaging and disposal.  
36 OIG,  FDA Lacks Comprehensive Data To Determine Whether Risk Evaluation and Mitigation  Strategies Improve Drug Safety,  
OEI-04-11-00510, February 2013.  
37 FDA has implemented four OIG recommendationsthose for it to (1) evaluate the Elements to Assure Safe  Use of one REMS 
each year as required by law; (2) to identify incomplete drug manufacturer assessments and work with drug manufacturers to 
obtain missing information; (3) to develop and implement a plan to identify, develop, and to validate, and assess REMS 
components; and (4) clarify expectations for sponsors assessments in FDA assessment plans.  The statuses of the open  
recommendations were current as of April 2020.  
38 The third-party administrator of the TIRF REMS conducts the surveys.  The administrator stated that confidence intervals  
were 53.2 percent to 64.5 percent for prescriber results,  and 41.2 percent to 52.8 percent for pharmacist results.  
39 FDA,  Review of the fifth (48 month, October 29, 2014 to October 28, 2015) Risk Evaluation and Mitigation Strategy (REMS)  
Assessment Report for Transmucosal Immediate Release Fentanyl (TIRF) Agents, p. 89, December 4, 2017.  
40 Data submitted by the TIRF manufacturers showed that 3.9 percent of deaths occurred in patients taking the drug off-label, 
53.5 percent occurred in patients taking the drug for unknown indications, and only 42.6 percent occurred in patients taking 
the drug for cancer-related indications.  
41 The drug manufacturers analyses were done by each individual TIRF drug.  The range represents the opioid nontolerance  
variability across drugs. 
42 FDA used its  FDA Adverse Event Reporting System (FAERS).   The FAERS data has limitations, such as there being no certainty 
that the drug in question caused the adverse event and the system not capturing every adverse event or prescription error.  
FDA told us that it has not found FAERS to be an effective tool to assess drug utilization patterns over time.    
43 FDA,  Review of the sixth (60 month, October 29, 2015 to October 28, 2016) Risk Evaluation and Mitigation Strategy (REMS)  
Assessment Report for Transmucosal Immediate Release Fentanyl (TIRF) Agents, p. 50, September 28, 2016.  
44 FDA told us that it eventually realized these data were inflated when analyzing the 84-month assessment, which was outside 
the scope of our review.  The inflated numbers did not change the veracity of the conclusions that FDA drew based on its 
analysis at the time.     
45 Alexander, G. Caleb, et al.,  Testimony for the Record Submitted to the U.S. Food and Drug Administration for the Joint Meeting 
of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory  
Committee, Docket No. FDA-2018-N-1917, August 3, 2018.  The same researchers published their findings the following year.  
See Rollman, Jeffrey Eric, et al., Assessment of the FDA Risk Evaluation and Mitigation Strategy for Transmucosal Immediate-
Release Fentanyl Products,  Journal of the American Medical Association, Volume 321, Number 7, February 19, 2019.  
46 Transcript for the Joint Meeting of the Drug Safety and  Risk  Management Advisory Committee and the Anesthetic and 
Analgesic Drug Products Advisory Committee, August 3, 2018, pp. 334-347.  
47 Ibid., p. 292.  
48 Heyward, James, et al., Evaluation of the Extended-Release/Long-Acting Opioid Prescribing Risk Evaluation and Mitigation 
Strategy Program by the US Food and Drug Administration: A Review,  Journal of the American Medical Association, published 
online December 31, 2019.  Accessed at https://jamanetwork.com/journals/jamainternalmedicine/article-
abstract/2757791?resultClick=1 on January 7, 2020.  
 
 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Endnotes | 40  
   
 
49 The 24-month reviews for both REMS were the first to contain detailed data to address the goals.  
50 At an FDA advisory committee meeting on May 4, 2016, the vote was nearly unanimous in favor of mandatory training for 
prescribers of ER/LA opioids.   See https://www.fda.gov/media/100444/download, accessed on February 11, 2020.  FDA decided 
not to take the recommendation of the advisory committee, citing burden to the health care industry.   
51  State of Oklahoma  vs. Purdue  Pharma, No. CJ-2017-816 (filed August 26, 2019).  Accessed at 
https://nondoc.com/2019/08/26/read-the-full-johnson-johnson-opioid-ruling-from-judge-thad-balkman/ on December 20,  
2019.  
52 A drug may be deemed to be  misbranded if it is subject to a  REMS and the drug manufacturer fails to comply with a  
requirement of the REMS.  FD&C Act  502(y).  Misbranded drugs may not be introduced into, delivered, or received into  
interstate commerce.  FD&C Act  301 (a) and (c).    
53 Drug manufacturers that violate REMS requirements may be subject to civil monetary penalties of up to $250,000 per  
violation.  Civil monetary penalties are not to exceed $1 million in a single proceeding.  Civil monetary penalties may increase 
to $10 million for continued violations.  FD&C Act  303(f)(4)(A).  
54 Press Release, Department of  Justice, Founder and Four Executives of Insys Therapeutics Convicted of Racketeering 
Conspiracy, May 3, 2019.  Accessed at https://www.justice.gov/usao-ma/pr/founder-and-four-executives-insys-therapeutics-
convicted-racketeering-conspiracy on June 30, 2020. 
 
FDAs Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis    
OEI-01-17-00510   Endnotes | 41