Development and Regulation of Abuse-Deterrent Formulations of Opioid Medications; Public Meeting
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Notice of public meeting; request for comments.
Citation: "79 FR 56810"
Document Number: "Docket No.
Page Number: "56810"
"Notices"
SUMMARY:
DATES: The public meeting will be held on
ADDRESSES: The public meeting will be held at the
Submit electronic comments to http://www.regulations.gov. Submit written comments to the
FOR FURTHER INFORMATION CONTACT:
SUPPLEMENTARY INFORMATION: Opioid analgesics are important medications that are widely prescribed for the treatment of pain, and certain opioids are also used in drug treatment programs. When used properly, opioid drugs provide significant benefits for patients. However, they also carry a risk of misuse, abuse, addiction, overdose, and death. According to an analysis from the
The development of and transition to use of opioids with meaningful abuse-deterrent properties is one important component of a multipronged approach to addressing abuse of opioid medications.
To achieve this goal,
FDA understands that the iterative innovation in abuse-deterrent technologies we envision could have implications for generic opioid medications. It is important that generic options remain available to ensure widespread access to effective analgesics for patients who need them.
The transition to abuse-deterrent formulations of opioid medications presents a number of complex scientific and regulatory challenges. The purpose of this public meeting is to share and solicit comments on the Agency's ongoing work to identify and address these challenges.
II. Background
Opioid analgesics (e.g., hydrocodone, oxycodone, morphine, and fentanyl) play a vital role in treating both chronic and acute pain.
Unfortunately, the abuse and misuse of opioid medications has become a public health crisis. Opioid-involved drug overdose death rates in
As part of this work,
FDA believes abuse-deterrent technologies can and will improve substantially and can make a real impact in the fight against prescription opioid abuse.
* Established an
* Consulted with advisory committees in connection with the development, evaluation, and labeling of opioids with abuse-deterrent technologies. For example, in
* Issued draft guidance to assist industry in developing and assessing abuse-deterrent opioid formulations ("Draft Guidance for Industry: Abuse-Deterrent Opioids--Evaluation and Labeling," 78 FR 2676;
* Met and worked with sponsors regarding approval of potentially abuse-deterrent formulations and reviewed applications seeking approval, or, subsequent to such approval, seeking inclusion of language in product labeling regarding the products' purportedly abuse-deterrent properties.
* Determined that the original formulation of OXYCONTIN posed an increased potential for abuse by certain routes of administration compared to reformulated OXYCONTIN. Based on the totality of the data and information available,
* Conducted or supported research on opioid formulations designed to deter abuse. This includes development of in vitro testing methodologies to assess purportedly abuse-deterrent opioid formulations.
* Sought public comment on innovative packaging, storage, and disposal systems that could help deter prescription opioid abuse (see http://www.gpo.gov/fdsys/pkg/FR-2014-04-09/pdf/2014-07909.pdf).
III. Scope of the Public Meeting
FDA is opening a docket and holding a public meeting to obtain public input on issues related to abuse-deterrent formulations of opioid medications. The first session of the meeting will focus on scientific and technical issues related to the development and in vitro assessment of these products. The second session will focus on
A. Session 1: Development and Evaluation of Abuse-Deterrent Opioid Formulations
In this session
FDA will discuss its internal research in this area. This discussion will include the manufacturing science behind the design of abuse-deterrent formulations, a variety of manipulation techniques, and the results of testing approved products and placebo formulations under a range of different manipulation conditions.
FDA is developing standardized in vitro test methodologies to assess how well purportedly abuse-deterrent formulations perform under conditions designed to simulate the ways individuals who abuse opioids manipulate opioid products for purposes of abuse (e.g., crushing, heating, dissolving).
For both NDAs and ANDAs, these methodologies could be used to identify the critical performance attributes of the drug potentially related to abuse-deterrence (e.g., crush-resistance, extraction-resistance). For NDAs, these methodologies could be used to assess comparative performance with predecessor products or appropriate controls (e.g., a non-abuse-deterrent immediate-release (IR) formulation with the same active ingredient). For ANDAs,
For both NDAs and ANDAs,
Topics for Discussion:
* Please comment on the limitations of currently available abuse-deterrent technologies and what next-generation technologies or products might be able to overcome these limitations and provide improved protection against abuse and misuse. Please comment both on the development of iterative improvements in abuse-deterrent technologies for solid oral dose forms of opioids and on the development of abuse-deterrent formulation technologies for non-solid oral dosage forms (e.g., transdermal patches, solutions, and buccal films).
* Please comment on the approach discussed above whereby
* Please comment on the approach discussed above whereby
* Specifically, please comment on the utility of step-wise testing, moving from simple manipulations to more complex ones. If the abuse-deterrent features are compromised or defeated by simple manipulations, would further testing that is more complex (e.g., involving more than one manipulation) and more destructive (e.g., higher temperatures, harsher solvents, etc.) be valuable?
* Please also comment on the availability and use of common solvents in which extraction studies should be conducted.
* Please comment on the appropriate controls for in vitro assessments of proposed generic abuse-deterrent formulations. Should the proposed generic abuse-deterrent formulation only be compared with the RLD formulation with abuse-deterrent properties or is the use of an additional negative control necessary to ensure that the test is sufficiently discriminatory? Please comment on the selection and standardization of a negative control, and what degree of superiority compared with the negative control should be viewed as meaningful.
* Please comment on what performance attributes should be considered "critical" in assessing whether and to what extent a formulation effectively deters abuse, such as the time delay or the amount of effort needed by the abuser under controlled conditions to access the drug for purposes of abuse. How can these performance attributes be quantified and linked to their impact on abuse deterrence? For example, an abuse-deterrent technology may only delay--rather than completely prevent--access to the opioid for purposes of abuse. Please comment on the amount of time delay that should be considered significant and the basis for your recommendation.
* Please comment on how
FDA assesses each opioid drug product's safety and efficacy on a case-by-case basis. Abuse potential is one aspect of a product's safety that the Agency considers, together with all other appropriate factors, in determining whether a product's benefits outweigh its risks. As part of this determination,
For instance,
Regarding the labeling of opioid products with potentially abuse-deterrent properties,
Regarding generic versions of opioids designed to deter abuse,
As abuse-deterrent technologies continue to improve and new opioid products are developed and approved that meaningfully reduce abuse,
Although FDA has received requests to require all opioid medications, or some subset of them, to be formulated with abuse-deterrent technologies, we have said that a class-wide requirement is not feasible or in the interests of public health at this time (Ref. 9). This field is still in its early stages. Both the technologies involved and the clinical, epidemiological, and statistical methods for evaluating those technologies are new and rapidly evolving. As discussed above, we have limited experience with these formulations and currently available abuse-deterrent technologies have significant limitations.
Accordingly,
Finally, given that currently marketed abuse-deterrent technologies have significant limitations,
Topics for Discussion:
* As described in the "Draft Guidance for Industry: Abuse-Deterrent Opioids--Evaluation and Labeling,"
* What does it mean for a product to have meaningful abuse-deterrent properties? Please comment on what data should be provided to support that determination.
*
* One aspect of the benefit/risk assessment relates to the consideration of available therapies. Please comment on
* Much of the focus in developing abuse-deterrent formulations has been on extended-release and long-acting (ER/LA) opioids. As more ER/LA opioid products are reformulated with abuse-deterrent technologies, individuals who abuse opioids may shift their attention to opioid drugs lacking abuse-deterrent properties, including IR products. Are there special considerations associated with IR products that do not apply to ER/LA opioids? Also, please comment on whether there are subclasses of opioid medications for which a shift to abuse-deterrent formulations may be of limited public health benefit.
* As discussed above,
* If FDA were to determine that the risks of an opioid product--or, in the case of a class-based approach, many such products--that lacks abuse-deterrent properties outweigh the benefits in light of available therapies, how could the Agency minimize any negative impact on patient access and on generic and innovator drug development? One possible option would be to apply a delayed implementation date (e.g., 2 years) to give affected sponsors a "phase-out" period to either reformulate or withdraw products lacking abuse-deterrent properties. Please comment.
* As noted above,
* Finally,
III. Attendance and Registration
Attendance is free and will be on a first-come, first served basis. Individuals who wish to present at the public meeting must register on or before
Individuals who wish to attend the meeting but do not wish to make a presentation should also register at https://fda-abuse-deterrent-public-meeting.eventbrite.com by
If you need special accommodations due to a disability, please contact
Information about how to view the live Web cast of this meeting will posted at http://www.fda.gov/Drugs/NewsEvents/ucm408607.htm. A video recording of the meeting will be available at the same Web address for 1 year.
IV. Comments
Interested persons may submit either electronic comments regarding this document to http://www.regulations.gov or written comments to the
V. Transcripts
As soon as possible after a transcript of the public meeting is available, it will be accessible at http://www.regulations.gov. It may be viewed at the
VI. References
The following references have been placed on display in the
1. CDC, "Opioids Drive Continued Increase in Drug Overdose Deaths", 2013, available at http://www.cdc.gov/media/releases/2013/p0220_drug_overdose_deaths.html.
2. SAMHSA,
3. SAMHSA,
4. SAMHSA, "Results from the 2012
5.
6. CDC, "Vital Signs: Overdoses of Prescription Opioid Pain Relievers--United States, 1999-2008," available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6043a4.htm.
7.
8. "Draft Guidance for Industry: Abuse-Deterrent Opioids--Evaluation and Labeling,"
9.
Dated:
Assistant Commissioner for Policy.
[FR Doc. 2014-22514 Filed 9-22-14;
BILLING CODE 4164-01-P
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