By guest author, Stacey L. Sklaver, Esq
A consortium of 4 groups has petitioned the U.S. FDA to reject non-abuse-deterrent opioid analgesics and, separately, to end the abstinence-only stance regarding approval of medications used for addiction treatment.
On June 11, 2013, the Center for Lawful Access and Abuse Deterrence (CLAAD), National Association of Drug Diversion Investigators, National Family Partnership, and Ryan’s Cause submitted a Citizen Petition to the U.S. Food and Drug Administration (FDA) [PDF available here]. The petition asks the FDA to foster a transition to abuse-deterrent opioids and promote greater treatment for opioid addiction, specifically through Medication-Assisted Treatment (MAT) — requests that are aligned with Obama Administration policy.
In order to accomplish these goals, the Petition asks the FDA to take 3 administrative actions:
- reject applications for new and generic opioid medications lacking abuse-deterrent features;
- acknowledge that patients tend to benefit from medication-assisted treatment (MAT) for substance abuse in various ways aside from staying drug-abstinent for prolonged durations; and
- provide additional guidance to the pharmaceutical industry that explains the requirements necessary for obtaining FDA approval and recognition as an abuse-deterrent opioid.
The Petition comes as part of coordinated efforts to reduce opioid abuse while protecting access to high quality health care. In 2010, approximately 16,651 people in the United States died as result of unintentional overdoses involving prescription opioid pain relievers. Opioids contribute to the epidemic because they are often chewed, crushed, cut, grated, or grinded, resulting in overdoses, addictions, and even deaths.
As a result, the Executive Office of the President and federal agencies have supported a transition to abuse-deterrent opioids, which are designed to make product manipulation more difficult or to make abuse of the manipulated product less attractive or rewarding. The Executive Office and various federal agencies also called for expanding access to addiction treatment, and more specifically, have prioritized MAT, an approach that uses FDA-approved pharmacological treatments in combination with psychosocial treatments, for patients with substance use disorders. Taking heed of such policies, pharmaceutical companies have begun developing and marketing medications incorporating novel technologies intended to thwart certain forms of abuse and to promote MAT.
Yet, despite federal policy and industry compliance with such policy, the Petition identifies a major problematic trend in the FDA’s recent decision-making: FDA actions, as of late, indicate that the agency is not acting in a manner that adequately reflects the urgency of the prescription drug abuse epidemic, and that the FDA is not optimally exercising its regulatory authority to advance Obama Administration policies supporting a transition to abuse-deterrent opioids, patient access to addiction treatment, and more specifically, MAT. The Petitioners use the FDA’s recent decisions on oxycodone, oxymorphone, and a new buprenorphine subdermal implant to illustrate this point.
Recent FDA Actions
The manufacturer of oxycodone — a medication used to manage moderate to severe pain — replaced the extended-release formulation (“OC”) of its medication with an abuse-deterrent extended-release oxycodone (“OCR”) formulation because OC was often intentionally abused and inadvertently misused, but OCR was more difficult to manipulate. When other drug manufacturers submitted applications proposing to reintroduce the more readily abused OC in generic form back to the market, the manufacturer of OCR asked the FDA to prevent this from happening.
On April 16, 2013, the FDA concluded that OC was withdrawn from sale for safety reasons due to OCR’s lower potential for abuse than OC, and, as a result, the FDA barred generic versions of OC that lack abuse-deterrent features from the market. The decision established that the FDA recognizes that an opioid’s benefit/risk profile can change due to the availability of an alternative product with a lower potential for abuse.
Subsequently, the manufacturer of oxymorphone also realized that its original formulation of extended-release oxymorphone (“OP”), an opioid for the treatment of pain, was frequently misused and abused. As a result, it too produced a new extended-release oxymorphone (“OPR”) containing abuse-deterrent technology described as virtually identical to that used in OCR, discontinued its original formulation, and petitioned the FDA to determine that OP was removed for safety and effectiveness reasons.
However, on May 10, 2013, the FDA ruled that there was insufficient data to conclude that OPR offered safety advantages over OP, and refused to find that OP was withdrawn from sale for safety reasons. The FDA based its decision on shortcomings in data regarding OPR’s reduced potential for abuse.
The FDA stated that while it considers the development of abuse-deterrent formulations a high public health priority, such properties must be supported by adequate data, and it emphasized the importance of a case-by-case determination taking into account the totality of the evidence for a particular drug at issue. The decision allowed generic versions of OP that lack abuse-deterrent features to remain on the market and expressly stated that additional generic versions of the discontinued OP may be approved.
In other action, a manufacturer of buprenorphine developed an abuse-deterrent subdermal implant designed to provide a therapeutic level of buprenorphine to an opioid-dependent patient for up to 6 months in order to treat addiction. A study in the Journal of the American Medical Association heralded the implant as an important advancement in opioid addiction treatment, leading the National Institutes of Health (“NIH”) in 2009 to award the manufacturer a 2-year grant in the amount of $7.6 million.
Separately, the U.S. Office of National Drug Control Policy (ONDCP) stated that the buprenorphine implant has the potential to eliminate the need for a daily dose of buprenorphine and reduces the potential for diversion and abuse. The FDA’s Psychopharmacology Drugs Advisory Committee voted for approval of the medication, recognizing the favorable benefit-risk profile.
Yet, on May 1, 2013, the FDA withheld approval for the medication, informing the manufacturer that it must submit new clinical data to establish the medication’s effectiveness for the FDA to reconsider the application. Specifically, the FDA stated: “Even after allowing 4 months for engagement in treatment, only 3 [buprenorphine implant]-treated patients were fully abstinent from opioids.”
These facts indicated that the FDA was not acting in a manner that adequately reflects the urgency of the prescription drug abuse epidemic. Furthermore, the agency was not optimally exercising its regulatory authority to advance the Obama Administration policies supporting a transition to abuse-deterrent opioids, patient access to addiction treatment, and more specifically, to MAT.
The Petitioners oppose the FDA’s May 10, 2013 decision to allow the introduction of more non-abuse-deterrent OP (extended-release oxymorphone) generics to the U.S. market. They argue that allowing applications for generic versions of non-abuse-deterrent opioids to proceed wastes limited FDA resources, undercuts progress made by removing such medication from the market, and poses severe public health and safety threats.
It also creates a disincentive for manufacturers to invest in costly R&D of novel technologies to reduce prescription drug abuse and treat drug addiction, only to be undercut in a two-fold manner; first, by a federal regulatory body that does not fully exercise its authority to foster a market transition to abuse-deterrent opioids and, secondly, by competitors intent on profiting from formulations that are more easily abused. Rather than increase the availability of widely abused prescription drugs, as the FDA is poised to do based on its May 10, 2013 decision, the Petitioners ask the FDA to approve only applications for opioids for which predictive or determinative data support the products’ potential to reduce abuse.
The Petitioners also disagree with the FDA’s decision to withhold approval for the buprenorphine implant, an abuse-deterrent medication used in MAT. The FDA’s rationale for its decision — that the implant does not result in abstinence among treated patients — is inconsistent with established scientific-medical principles showing that MAT typically does not yield prolonged abstinence, but that it does yield a higher rate of other kinds of success.
Instead, the Petitioners argue that abstinence should not be the exclusive clinical outcome the FDA considers when assessing the effectiveness of a pharmacotherapy for use in MAT. The Citizen Petition states “No medication is appropriate or yields optimal results for all patients, but it is nonetheless imperative to bring to market those medications that provide some clinical benefit for some patients.”
Failing to acknowledge the wide array of potential clinical benefits of MAT, and relatedly withholding approval for abuse-deterrent medications to treat opioid dependence, can have devastating effects on pharmaceutical companies. This, in turn, may further slow the transition or even reverse progress toward the adoption of abuse-deterrent medications in the marketplace.
The Petitioners also ask the FDA to provide additional detailed guidance to industry, on a case-by-case basis or otherwise, regarding the agency’s expectations for assessments of clinical benefits and abuse deterrence. Such guidance will help the pharmaceutical industry to proceed swiftly and with greater clarity as to scientific and regulatory requirements necessary to develop and commercialize abuse-deterrent products. Additionally, if the FDA has previously denied a drug sponsor’s application or petition for a determination on a reformulated product, the agency should prioritize and expedite its ongoing dialogue with the manufacturer and follow-on product review.
By taking these 3 steps, the Petitioners argue, the FDA can advance Obama Administration policy and reflect the urgency of the prescription drug abuse epidemic.
The FDA has 180 days from the date the Petition was submitted to respond to the Petitioners. In the meantime, readers can support the Petition by filing comments for the FDA’s consideration. To ensure the FDA accepts the comments, supporters should include the specific verification language found in 21 U.S.C. § 355(q)(1)(i) and sign the comment. The comments may be mailed to the following address:
Division of Dockets Management
Food and Drug Administration
5630 Fishers Lane
Room 1061, HFA-305
Rockville, MD 20852
Readers may also submit comments electronically once the Petition has been posted to www.Regulations.gov, which is anticipated to take place by June 21, 2013. Instructions for submitting an online comment can be found [here]. The Petition’s docket number is FDA-2013-P-0703. For further information, please contact CLAAD at firstname.lastname@example.org.
- Press Release, Centers for Disease Control and Prevention, Opioids Drive Continued Increase in Drug Overdose Deaths (Feb. 20, 2013), available [here].
- FDA Acts to Reduce Harm from Opioid Drugs, FDA Consumer Health Information, available [PDF here].
- Guidance for Industry: Abuse-Deterrent Opioids—Evaluation and Labeling, FDA (Jan. 2013) available [PDF here].
- National Drug Control Strategy, Office of National Drug Control Policy (2013), available [PDF here].
- Oxycodone (Oxycodone Hydrochloride) Drug Products Covered by New Drug Application 20-553 Were Withdrawn from Sale for Reasons of Safety or Effectiveness, 78 Fed. Reg. 23273, 23274 (FDA Apr. 18, 2013) (determination).
- Response to Citizen Petition, Docket No. FDA-2012-P-0895 (May 10, 2013), available [here].
- Endo Pharmaceuticals Inc. v. U.S. Food & Drug Administration, 1:12-cv-01936 (D.D.C. Nov. 20, 2012).
- FDA Psychopharmacologic Drugs Advisory Committee, Probuphine, (Mar. 21, 2013), available [PDF here].
- Important Events in NIDA History, National Institutes of Health, available [here].
- Press Release, Titan Pharmaceuticals Announces FDA Advisory Committee Recommends Approval of Probuphine for the Treatment of Adult Patients with Opioid Dependence, Titan Pharmaceuticals, Mar. 21, 2013, available [here].
- John Carroll, Updated: FDA Steamrolls Over Panel Vote, Spurns Titan’s Addiction Drug Probuphine, FierceBiotech, May 1, 2013, available [here].
- Brief of Center for Lawful Access and Abuse Deterrence as Amici Curiae Supporting Plaintiff, Endo Pharmaceuticals Inc., v. U.S. Food & Drug Administration, No. 1:12-cv-01936 (2012).
- These include retention in treatment, reduction in illicit substance use, improved psychiatric status, greater social adjustment, and increase in functional state and quality of life, among other things. See for example: T.V. Parran, et al., Long-Term Outcomes of Office-Based Buprenorphine/Naloxone Maintenance Therapy, 106 Drug & Alcohol Dependence 56 (2010); Icro Maremmani, et al., Substance Use and Quality of Life Over 12 Months Among Buprenorphine Maintenance-Treated and Methadone Maintenance-Treated Heroin-Addicted Patients, 33 J. of Substance Abuse Treatment 91 (2007).; Mary Jeanne Kreek, et al., History and Current Status of Opioid Maintenance Treatments: Blending Conference Session, 23 J. of Substance Abuse Treatment 93 (2002); Miranda W. Langendam, et al., The Impact of Harm-Reduction-Based Methadone Treatment on Mortality Among Heroin Users, 91 Am. J. of Pub. Health 774, No. 5 (2001); G.K. Hulse, et al., The Quantification of Mortality Resulting from the Regular Use of Illicit Opiates, 94(2) Addiction 221 (1999); D. Dwayne Simpson, et al., Drug Abuse Treatment Retention and Process Effects on Follow-Up Outcomes, 47 Drug & Alcohol Dependence 227 (1997); S. Darke et al., Fatal Heron “Overdose”: a Review, 91:30 Drug Addiction 327 (1996); J.R.M. Caplehorn, et. al., Retention in Methadone Maintenance and Heroin Addicts’ Risk of Death, 89 Addiction 203 (1994); M. Davoli et al., Risk Factors for Overdose Mortality: A Case-Control Study Within a Cohort of Intravenous Drug Users, 22 Int’l J. Epidemiol 273 (1993); L. Gronbladh, et al., Mortality in Heroin Addiction: Impact of Methadone Treatment, 82 Acta Psychiatry Scand. 223 (1990); Russell K. Portenoy, et al., Chronic Use of Opioid Analgesics in Non-Malignant Pain: Report of 38 Cases, 25 Pain 171 (1986).
- 21 C.F.R. 10.30(e)(2).
- See 21 C.F.R. 10.20.
- For the verification language, see 21 U.S.C. 355(q)(1)(I) [here].
About the Author: Stacey L. Sklaver is an attorney at DCBA Law & Policy. Her greatest strengths lie in conducting research and providing analysis of laws, regulations, and courts’ interpretations of such in the areas of health and pharmaceutical law. Ms. Sklaver’s written work products include published law review articles, formal agreements, court filings, and legal memoranda. She is a graduate of George Mason School of Law, where she served as articles editor for the George Mason Law Review. She earned her bachelor’s degree in English and graduated summa cum laude from Boston’s Suffolk University in 2006.
Editor’s Proviso: All observations, opinions, advice, or facts expressed above are those of the guest author, and do not necessarily reflect the positions of Pain Treatment Topics, our staff and advisors, or our educational supporters/sponsors. Opposing views, opinions, or clarifications regarding this UPDATE article are welcomed in comments below or by separate submission for consideration of publication.
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