December 21, 2017
Dockets Management Staff (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852.
National Center for Health Research’s Public Comment
on Opioid Policy Steering Committee
[Docket no. FDA-2017-N-5608]
Thank you for the opportunity to provide comments on the FDA’s newly established Opioid
Public Steering Committee (OPSC). The National Center for Health Research (NCHR) is
nonprofit research center focused on research, policies, and programs that affect public health.
Our Center analyzes scientific and medical data and provides objective health information to
patients, providers, and policymakers.
Our nation faces an opioid crisis of epic proportions. This crisis stems from too many
prescriptions; false and misleading marketing; insufficient oversight and regulatory control;
inadequate risk mitigation; and insufficient public health and social services infrastructures. We
applaud the FDA for addressing their role in developing strategies to “confront” the opioid crisis.
We agree that the magnitude and scope of this crisis requires urgent action and agree that the
FDA should consider patients’ and other relevant groups’ interests in developing effective
approaches to reduce further harm from opioids.
We urge the FDA to consider the following three recommendations:
1) Be more specific and accurate when claiming that a drug is abuse-deterrent. For
example, if a drug is crush-resistant, or difficult to crush in a specific way, it should be labeled as
“crush-resistant” — not as “abuse-deterrent.” “Crush-resistant” provides a simple, clear, and
specific description of what the drug deters. Only those drugs that significantly reduce the
chances of abuse should be designated with such a label, and the reasons for that label should be
clearly explained. In July at the FDA’s Public Meeting on Abuse Deterrent Opioids,
Commissioner Gottlieb stated, “…we don’t want to improperly convey a perception that a
product that is resistant to manipulation and abuse is somehow also less prone to fueling
addiction, when that is simply not true.” We agree and urge the FDA to follow through with a
change in policy regarding the terminologies used.
Labeling a drug as abuse-deterrent influences prescribers, patients, and family members.
Research indicates that many physicians believe that a drug labeled “abuse deterrent” is less
addictive. In addition, there is currently no industry standard constituting physical or chemical
properties of abuse deterrence. Does the drug have a high melting point, and therefore can’t be
liquefied for IV injection? Does the drug have a hard shell and can’t be crushed for nasal
snorting? Does the drug create a noxious substance when abused? Any of these properties could
deter abuse; however, a drug possessing one of these properties may still be abused through
another mechanism. Providing a drug with a blanket designation such as “abuse deterrent”
falsely misleads consumers and prescribers into believing that all means of potential abuse have
been tested when that is not the case. Therefore, we urge the FDA to use plain language and
indicate on the label exactly what the formulation deters.
We support the FDA’s interest in labeling drugs that deter abuse, but we agree with FDA
scientists that some drugs marketed as “abuse deterrent” were actually highly abused, misused,
and diverted. Post-market surveillance played a critical role in identifying the unintended and
devastating consequences due to intravenous abuse of Opana ER. Labeling Opana ER as
abuse-deterrent when it was actually widely abused contributed to the problem by misleading
prescribers, patients, and family members. The FDA states that a product that has abuse-deterrent
properties means that “the risk of abuse is lower than it would be without such properties.” We
urge the FDA urgently review the evidence for any drug that is currently labeled as abuse
deterrent to ensure that the designation be held to this standard. And, of course, any new drugs
should also be held to that high standard.
2) Require a minimum of 2 well designed studies to assess the efficacy and safety of opioid
related products. The FDA plays a powerful role in approving these drugs, and thus it is critical
for the FDA to make approval decisions based on sound science and strong data. This includes
adherence to the FDA’s Guidance for Industry on Abuse-Deterrent Opioids, which states that
premarket studies be “scientifically rigorous.” This is the only way to determine the potential
real-world impact of opioid formulations intended to deter abuse.
To confront the opioid epidemic, the FDA must hold pharmaceutical companies to a higher
standard and require clear evidence of a drug’s efficacy and safety. For abuse-deterrent
formulations, the FDA should require sufficient evidence that the drug’s abuse-deterrent
properties result in meaningful reductions in abuse, misuse, and related adverse clinical
outcomes. We testified at the July FDA meeting against abuse-deterrent labeling for IPC Oxy
because the drug had not been investigated with physicochemical and clinical abuse potential
studies. We urged then and continue to urge the FDA to not use a lower standard for approval
than indicated in their Guidance for Industry.
The FDA should work with sponsors to develop well-designed trials that reflect real-world use
and also maintain scientific rigor. With regards to medication-assisted treatments (MAT),
efficacy endpoints need to be clearly defined, assessed over a longer time course, and meaningful
to patients.
● Measurements need to be internally valid, because self-reported data may not be
accurate measures of illicit drug use and are subject to bias.
● Sponsors should be required to collect information regarding the safety of the drug in
patients with liver or kidney impairments, as many with opioid use disorder (OUD) have
comorbid chronic hepatitis and other chronic diseases.
● Since clinical trials represent a “perfect world” scenario for intended use, and
real-world experiences might be quite different, patient selection and use of the drug must
be reflective of the real-world.
3) Improve REMS training using 2 major strategies: make it a requirement, and have the
training evaluated by FDA scientists to make sure that it is effective in terms of outcomes
that matter. Based on previous research, the FDA knows that most prescribers do not participate
in the voluntary training, that many who start the online training don’t complete it, and that even
those that complete it don’t learn all the most essential lessons the training is intended to teach. 1,2
Given that track record, it is unlikely that current voluntary REMS, which was expanded to
include prescriptions of immediate release opioids, are effective at reducing either inappropriate
prescribing, abuse, or diversion. The law requires the FDA to review sponsors’ assessments of
REMS, but does not require an independent assessment of REMS by the FDA. The FDA should
evaluate the impact of REMS for opioids annually, given the current epidemic, and change the
REMS strategies to ensure they are more effective. This is particularly important because
industry-sponsored REMS training poses an inherent conflict of interest, and has clearly been
inadequate. Moreover, a study of providers by Boston Medical Center 3 found that training that
follows the FDA Blueprint for Prescriber Education failed to provide prescribers with adequate
information on safe opioid prescribing, managing pain with non-opioid drugs, and regulations
regarding opioid prescribing.
Currently, we must rely on the drug sponsor to accurately assess its own REMS programs but the
data are not publicly available. Those evaluations should be made public immediately. We agree
with the assessments panel members made at the May 3-4, 2016 Advisory Committee Meetings,
when they pointed out that the program was “inadequately evaluated. 4 ” Rather than focusing
assessments on the effectiveness of REMS to meet outcomes of interest (reducing addiction,
overdose, deaths), evaluations focused on “secondary measures of prescriber education. 4 ” Both
are important, and it seems that the current REMS are insufficiently achieving either of those
goals. We strongly urge that FDA perform independent assessments of the effectiveness of
opioid REMS to meet meaningful objectives, and make those assessments publicly available so
that stakeholder shave access to information about the REMS programs’ effectiveness and work
toward improving them.
We appreciate your consideration of our views and urge you to focus on strategies based on the
sound science, reliable data, and public health.
Sincerely,
Diana Zuckerman, PhD
President
National Center for Health Research
Footnotes:
1. Medpage Today. Opioid REMS Falls Short on Reaching Docs. (Apr. 28, 2016).Available
online: https://www.medpagetoday.com/neurology/painmanagement/57575
2. Medscape News. FDA Institutes REMS for Immediate-Release Opioids. (Jul. 11, 2017).
Available online: https://www.medscape.com/viewarticle/882763
3. Cushman PA, et al.What do providers want to know about opioid prescribing? A qualitative
analysis of their questions. Substance Abuse Journal. 2017. 38(2): 222-229.
doi.org/10.1080/08897077.2017.1296525
4. U.S. FDA. 2016 Meeting Materials, Drug Safety and Risk Management Advisory
Committee. (May 4, 2016 Transcript). Available online:
https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandR
iskManagementAdvisoryCommittee/ucm486856.htm