Dr. Sara Roach: Welcome to “Q&A with FDA,” from the FDA’s Division of Drug Information where we aim to answer some of the most frequently asked questions that we’ve received from the public. I’m Dr. Sara Roach, and today’s topic is the recent first generic approval to Vivitrol, a one-month extended-release injectable naltrexone that is used to help people recovering from opioid or alcohol dependence. I’m here with Dr. Iilun Murphy, Director of the Office of Generic Drugs in FDA’s Center for Drug Evaluation and Research (or CDER), and returning is Dr. Marta Sokolowska, CDER’s Deputy Center Director for Substance Use and Behavioral Health. Dr. Murphy and Dr. Sokolowska, thank you for being here today to discuss this very important approval.
Dr. Murphy: My pleasure.
Dr. Sokolowska: Thank you very much for inviting us.
Dr. Roach: This is such an important approval because it will help to increase access to treatment for opioid and alcohol use disorder at the time of record numbers of deaths related to drug overdoses.
Dr. Sokolowska: I couldn’t agree more. I have spoken on this podcast in the past about the Overdose Prevention Framework and overdose reversal agents. However, it is important to note that the rates of alcohol use disorder increased significantly since the onset of COVID-19, making this a major public health issue, though it’s not discussed as frequently as opioid overdoses. Over 140,000 Americans die from the effects of alcohol in an average year (more than from drug overdoses). Ten percent of Americans over the age of 12 have Alcohol Use Disorder. And according to the 2023 Alcohol Abuse Statistics, 60% of Americans increased their alcohol consumption during COVID-19 lockdowns.
Dr. Roach: These numbers are quite significant, so I’m glad we’re discussing this important public health issue. Could you tell me more about the FDA-approved drugs for the treatment of alcohol use disorder?
Dr. Sokolowska: For most patients treated with medication for alcohol use disorder, the decision to begin oral versus injectable naltrexone is based on patient’s preference, but injectable naltrexone may be more effective in ensuring adherence. Pharmacologic treatment of alcohol use disorder has been focused on altering the reinforcing effects of alcohol use. Naltrexone is available as an oral medication but also as the extended-release injectable product, Vivitrol, which has been approved since 2006.
Dr. Roach: Naltrexone is an opioid antagonist and is indicated for the treatment of alcohol dependence in patients who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment with the long-acting naltrexone injectable product. In addition, this medication is approved for the prevention of relapse to opioid dependence, following opioid detoxification, and should be part of a comprehensive management program that includes psychosocial support.
Dr. Sokolowska: Yes, it’s important because naltrexone is a treatment option for either disorder and is long acting. And by virtue of increasing the availability of generic drugs, it helps to create competition in the marketplace, which then helps to make treatment more affordable, increasing access to healthcare for more patients. Once-a-month extended-release injection reduces the dose frequency and therefore may be advantageous in helping ensure patients’ compliance, which is crucial to reduce potential relapse.
Dr. Roach: As you mentioned the brand name Vivitrol was approved in 2006, 17 years ago. Tell us about why the new generic to Vivitrol, the extended-release injectable naltrexone, is just now approved?
Dr. Murphy: Both Vivitrol and this first generic are complex drug delivery systems using biodegradable PLG [which is short for poly(lactide-co-glycolide)] polymers. The PLG polymer microsphere formulation allows for the month-long extended release of naltrexone. As you can imagine, the development, manufacture, and regulatory assessment of these biodegradable PLG polymer microspheres is generally much more complicated than that of the once daily oral tablet. Therefore time from concept of development of the product to marketing will take longer.
Dr. Roach: Since the first FDA approved PLG product more than 30 years ago there have been approximately 12 other approved products, and this is the first generic product that has PLG. So what is it that makes products using this PLG technology so complex?
Dr. Murphy: In order for a generic product to Vivitrol to be approved, it had to address several challenges in developing, manufacturing, and demonstrating that their naltrexone microsphere product was therapeutically equivalent to Vivitrol. One of these difficulties was selecting a PLG polymer that has comparable physicochemical and drug release properties to that brand product. These polymers are also biodegradable, which means that they break-up into components that can be naturally eliminated by the body. This is great in terms of overall product biocompatibility, but it also brings difficulty for generic development as some polymer properties can also be altered during the manufacturing process. So the selection, characterization, and manufacturing optimization of these products can give rise to considerable development resources being needed to reach success.
Dr. Roach: And what type of research went into the development of this product?
Dr. Murphy: The Office of Generic Drugs initiated its first research activities on PLG based long-acting products in 2013, shortly after the first implementation of Generic Drug User Fee Amendments (or GDUFA I for short). For our audience, Congress first enacted GDUFA in 2012, following negotiations between the FDA and industry and with input from the public stakeholders, to ensure patients have access to high-quality, safe, and effective generic drugs. User Fees enable FDA to bring greater predictability and timeliness to the review of generic drug applications. A portion of these user fees also fund the GDUFA Science and Research program that gives our office the resources to conduct research that facilitates industry’s development and CDER’s assessment of generic products. The two main focuses of our PLG research activities were to develop 1) analytical methods that can facilitate the reverse engineering, characterization, and the selection of PLG, which is a critical first step for generic drug development; and 2) in vitro drug release testing methods that improves understanding on how the drug may be released from the formulation and how different polymer and manufacturing induced characteristics affect drug release behavior. This enhanced understanding of formulation characteristics and drug release mechanism is important for guiding development of generic manufacturing and can significantly improve regulatory assessment efficiency. These research outcomes have been used to develop FDA’s product-specific guidances and address generic manufacturer inquiries during product development. The developed analytical methods have been shared with the generic industry via publications, workshops, and annual GDUFA research reports. And the generic industry has adopted these methods for supporting their generic drug development.
Dr. Roach: Dr. Murphy and Dr. Sokolowska, I appreciate you taking the time today to discuss this very important topic and the positive public health effects! Is there anything else you would like to mention or reinforce?
Dr. Murphy: The approval of generic Vivitrol sets a remarkable example for generic development of PLG based products. GDUFA research will continue to explore how modern analytical methods and modeling tools can be helpful for guiding product development and bioequivalence study design. The improved understanding of the design space for this group of products will provide a strong scientific foundation to explore novel approaches for product development and bioequivalence testing.
Dr. Sokolowska: I completely agree with Dr. Murphy. This is an important approval and aligns with our efforts to advance development of evidence-based treatments for substance use disorders.
Dr. Roach: Thanks for tuning in to “Q&A with FDA”. The full podcast and transcript of this recording is available at fda.gov/QAwithFDA. And if you have drug-related questions, reach out to us at firstname.lastname@example.org
- GDUFA Science and Research
- Overdose Prevention Activities Timeline
- Naltrexone for extended-release injectable suspension Information
- Alcohol Abuse Statistics