PA experts observing the recent marketing withdrawal of Opana ER (oxymorphone hydrochloride) considered other data that could be examined to determine if there is something inherent to the formulation that encourages more dangerous avenues of abuse, and the impact of other external factors on real-world safety.
On July 6, Endo Pharmaceuticals announced it would withdraw Opana ER from the market. This followed a March meeting of FDA’s Drug Safety Risk Management and Anesthetic and Analgesic Drug Products Advisory Committees in which committee members voted 18 to eight that the benefits of the formulation no longer outweigh the risks. Opana ER has been implicated in outbreaks of a Thrombotic Thrombocytopenic Purpura (TTP)-like illness in northeastern Tennessee and an HIV outbreak in southern Indiana. While Opana ER was not approved for labeling as abuse deterrent, Endo’s marketing of the product referenced the product’s formulation with Grunenthal’s INTAC® Technology which was intended to create a crush resistant product.
In the case of Opana ER, we note that other external factors potentially impacting the severity of the TTP and HIV outbreaks may have included how the drug was prepared for injection, other drugs injected with it, a shortage of syringes, criminal penalties (Indiana only) for possession of syringes, and lack of access to methadone/buprenorphine treatment.
Based on the publicly available information on Opana ER, companies may want to consider the following:
- Completing all abuse potential studies requested by the FDA
- Conducting heat pretreatment studies, with appropriate comparators
- Collecting and analyzing geographic-specific post-marketing surveillance data, including the collection of baseline data
- Conducting thorough surveillance, including field research, in the localities affected, to determine external factors potentially impacting these public health issues
PA scientists and experts prepare preliminary abuse potential assessments to determine gaps in the abuse potential assessment program, develop protocols for laboratory assessment of the abuse characteristics of product formulations, and develop and execute postmarketing surveillance, including field research.
Note: PA did not provide support to Endo on Opana ER development, abuse potential assessment, or regulatory strategy.
Kratom leaf-based products, from a South East Asian tree in the coffee family, are marketed as dietary supplements and often consumed in home brewed tea-like beverages or commercial products. Several million Americans consume kratom annually to increase alertness, enhance wellbeing and occupational performance. Kratom is also used as a natural remedy for several types of pain and, by an apparently rapidly growing number of people who had histories of opioid use, for pain and/or addiction – as a path away from opioids. On behalf of the American Kratom Association, PinneyAssociates developed a review of the scientific evidence regarding kratom’s effects according to the 8 factors of the Controlled Substances Act (CSA) to assist FDA and DEA in determining the most appropriate regulatory approach within FDA authority to permit appropriate use of kratom, as well as to minimize unintended effects, encourage research, and contribute to the enhancement of public health.
Our assessment, principally authored by Jack Henningfield and Reginald Fant, concluded that there is neither evidence that kratom is contributing to the opioid crisis or that kratom itself poses “imminent threat to public health” (the usual justification for emergency scheduling by the DEA). Furthermore, banning kratom could reasonably be predicted to produce public health problems that do not presently exist as the lawful kratom market would be replaced by a dangerous black market. Surveys suggest that if kratom were removed from the market many former opioid users benefiting from kratom (whether they had been using opioids to manage pain or because they had developed abuse or addiction problems) would return to use of opioids, licit and illicit. As stated by Dr. Henningfield, “This does not mean kratom products should not be regulated; to the contrary[,] we need reasonable and balanced regulation to reassure consumers that the ingredients of the products they purchase [are]… true to the product labels, that packaging and labeling are overseen by FDA, and that the lawful marketing of this life-line category of products is not taken away from those who have come to rely on it as an alternative to opioids and other substances.”
“Our work on kratom is an example of how we help regulators and industry make scientifically informed decisions about the risks and benefits of pharmaceuticals and dietary supplements,” said Dr. Henningfield. “Appropriate regulation and scheduling that considers multiple lines of evidence could help keep the risks low and the safety profile strong.”
Read the 8-factor assessment here.
Contact us to meet with a PinneyAssociates expert at these events.
Development of cannabinoid-based medicines is a rapidly growing area of interest for patients with unmet needs as well as the pharmaceutical industry. The path forward, however, is fraught with technical and regulatory issues that require a thoughtful approach early and throughout the development process.
At two recent medicinal cannabinoid conferences, CannMed 2017 and the 2017 International Cannabinoid Research Society (ICRS) Symposium, Michael Hufford and Daniel Wang presented their insights into federal regulations relevant to medicinal cannabinoids and how companies might begin to navigate these complex issues.
At the CannMed 2017 Conference, focused on the intersection of clinical application, medical research, cannabis-based therapeutics, cannabis safety and production, Michael Hufford and Daniel Wang separately presented on federal regulations relevant to medicinal cannabinoids.
Dr. Hufford described parallel regulatory changes between FDA expectations of respiratory drug delivery devices and regulatory and engineering challenges for the vaping and medicinal cannabis industry. Seen through the lens of pharmaceutical regulations, many existing respiratory delivery systems for medicinal cannabis and nicotine have multiple limitations, including variations in particle size leading to variable deposition and absorption and variable doses of compounds emitted both between devices, as well as within devices, over time. Engineering principles drawn from the field of respiratory drug delivery may help to address some of these concerns, including control of particle size and deposition, inhalation rates and resistance, timing of aerosol delivery, and paths to achieving consistency in emitted dose.
At CannMed and ICRS 2017, Mr. Wang described the influence of the Controlled Substances Act (CSA), in particular the role of the eight-factor assessment described in the CSA, as a starting point for the types of testing and outcomes that would likely be required to support placement of cannabinoid-based drugs in schedules less restrictive than Schedule I.
Both CannMed abstracts can be found here: http://www.cannmedevents.com/poster-presenters/
Scientific integrity: adherence to professional values and practices when conducting and applying the results of science1.
Dr. Bethea (Annie) Kleykamp presented at CPDD on the subject of scientific integrity, which impacts the behavior and is the responsibility of scientist researchers, as well as journalists, healthcare providers, industry executives, legislators, regulators, and patient advocates, among others.
“Open dialogue among individuals and organizations associated with drug abuse research is essential for ensuring that such research remains scientifically rigorous in the 21st century,” urged Dr. Kleykamp.
Active engagement of individuals and organizations in academia, industry, and government is essential for ensuring scientific integrity. Education for scientists and non-scientists should address issues including financial disclosures, non-financial conflicts of interest, communication of science to the general public, and principles of science such as critical thought and replication.
Read Dr. Kleykamp’s presentation here.
At the Global Forum on Nicotine in Warsaw, Poland, Dr. Hufford envisioned the future of recreational and therapeutic nicotine consumption. He invited attendees to consider the rapid evolution of electronic nicotine delivery devices and the role that excessive regulation could play in thwarting their beneficial public health impact. He framed these issues against a backdrop of the impact and pace of innovation and the potential consequences of regulation on the pace of innovation.
Joe Gitchell, PA President, offered brief remarks at the close of the conference and noted the tension between incomplete science and the need and desire to act, as well as the substantial challenges of observing any set of circumstances through any lens but one’s own. Change can be difficult and uncomfortable, but Mr. Gitchell called on participants to be willing to ask themselves difficult questions.
Dr. Hufford’s presentation can be found here: https://gfn.net.co/downloads/Presentations_2017_/Dr%20Michael%20Hufford.pdf
Watch Dr. Hufford’s presentation and Mr. Gitchell’s closing comments.