Reducing misuse and abuse is one of the more interesting
applications of formulation and drug delivery technology to real-world
challenges. Problems related to the abuse of central nervous system-acting
products are well known and yet remain a significant challenge for the medical
community, families, as well as law enforcement and the courts.
Serious attempts to reduce the abuse of prescription
drugs, most notably opioids, have been ongoing for more than a decade with some
significant advances realized. Yet there remains much to be done. From the
perspective of the pharmaceutical industry, there are at least two approaches
that promise at least some relief for this problem. The ideal solution from the
perspective of many is the development of increasingly well-tolerated novel
agents capable of treating indications such as pain, anxiety, depression, and
hyperactivity, without any abuse liability. This “holy grail” solution is yet
to be realized. The fallback approach has been to look to the pharmaceutical sciences
for ways to reduce the abuse and misuse of agents that have a long history of
efficacy and safety when used as prescribed. We will use the term
“abuse-deterrent” to describe these desired features and benefits. This
expression encompasses a wide variety of actions all related to reducing the
non-prescribed use of a product, in terms of intent or procedure.
We decided it would be interesting to interrogate the
PharmaCircle database and see what successes have been achieved with respect to
abuse-deterrent formulations in terms of approved and pipeline products. We
also took a more general look at the formulation approaches being applied to
Some background; this short review includes only products
and technologies that have reached the stage of clinical development. Research
and preclinical products, and their associated technologies, have not been
included. For the purpose of this article, some products that have not reported
results or activity for 4 or more years have been labeled as inactive, even
though the sponsoring companies may still list them in their product pipelines.
ABUSE-DETERRENT PRODUCT PIPELINE – APPROVED & CLINICALSTAGE PRODUCTS
the PharmaCircle Products & Pipeline database
with the terms “abuse-deterrent” and
“abuse-resistant” returned a total of 129 products as being at some stage of announced
development, marketed through clinical to preclinical and research. Limiting this list to products that are active and either approved, filed
with regulatory bodies, or in clinical
development reduces the number to a much more manageable list of 53 products. This excludes an additional 10 clinical products that have been formally discontinued or have provided
such limited updates to suggest they are in effect
discontinued. This list is current as of
distribution of these products by type and stage are summarized in Table 1. What is a little bit surprising is the number of generic abuse-deterrent products (19) that have received tentative approval or have their applications under review. The four approved products being targeted by these generics are Shire’s Vyvanse, Endo’s Opana ER Crush-Resistant, Acura’s Oxecta, and Purdue Pharma’s reformulated OxyContin.
take out the generics, there remain a
total of nine products that are Marketed,
Approved, or in Registration. A total of
seven products have been approved with a
direct or implied abuse-deterrent or abuse-resistant
claim. These products are listed in Table 2.
general formulation strategies are currently
employed to reduce or eliminate the
potential for the abuse and misuse of psychoactive
pharmaceuticals. These are:
Type 1- Formulations that physically limit the ability of products to be mechanically
or chemically modified for the
purpose of injection, insufflation, or rapid
Type 2 - Formulations that include
an antagonist or aversive agent that
blocks the desired properties of the product
when abused, or makes it unpalatable
or toxic when repurposed for
administration by injection or insufflation.
Type 3 - Modified
formulation-release products that limit the
possibility of rapid absorption of the active. This
can be achieved through some sort of
molecular modification (prodrug) or
sustained-release engineering not easily overcome using mechanical, physical, or kitchen chemistry procedures.
Type 4 - The fourth approach
combines two or more of the aforementioned approaches, most commonly some sort of modified-release combined with physical/chemical-resistance
features. The subcategories are:
Type 4a: Type 1 & Type 2
Type 4b: Type 1 & Type 3
Type 4c: Type 2 & Type 3
Type 4d: Type 1 & Type 2 & Type 3
analysis of the approved and clinical development pipeline as a function of technology
approach is presented in Table 3. (Note: generic products are not included in
this analysis.) Some assumptions were made regarding the exact abuse strategies
of certain pipeline products of which there was limited public information. A little
bit of explanation is in order to address what appear to be inconsistencies
with the figures in Table 3.
no “pure” Type 2 products in development as best as can be determined. The Type
2 strategy, incorporating an antagonist or aversive agent, is only seen in
combination with some sort of modified/extended-release technology. Of course,
extended-release, Type 3 was the original abuse-deterrent strategy until it was
realized that these products could be crushed, overcoming the modified-release characteristics
of the products and negating any abuse-prevention benefits. One immediate-release
development program using an aversive agent, niacin, as opposed to an
antagonist, was terminated after an FDA Advisory Panel suggested this approach
introduced safety issues.
At this point,
there are no approved or clinical-stage products identified as being Type 4d,
incorporating all three abuse-deterrent strategies, although there appear to be
a couple in the preclinical stage.
reader will note that there is a one-product discrepancy between Tables 1 and 3.
This is an outlier product, a transdermal formulation of fentanyl that makes
claim to reducing the potential for abuse by exhausting the fentanyl through efficient
delivery and leaving a negligible amount of active in the patch after the prescribed
3-day dosing. This makes the “used” patches less attractive for “smoking” or
extraction using kitchen chemistry techniques.
CONSIDERATIONS & GENERIC FORMULATIONS
to see how many 505(j) products are lined up at the US FDA waiting to capture
the generic opportunity represented by currently approved abuse-deterrent
products. The leading product from a units and revenue perspective, Purdue Pharma’s
OxyContin, is likely to be subject to generics as soon as October 2014 on the
basis of a settlement with Actavis. This agreement limits the number of units that
Actavis will be permitted to distribute after the FDA approves their generic.
question of the regulatory requirements necessary to secure a label claim of
abuse-resistant or deterrent is still not clear. Purdue managed to secure language
in its US product labeling for OxyContin that reviewed the abuse-deterrence studies
conducted for the product. This contrasts with the new formulation of Opana ER
from Endo that is identified as crush-resistant, but carries no abuse-resistant
or deterrent information in its package insert. Clearly, there is a minimal
amount of data that needs to be provided to secure abuse-resistant and/or deterrent
language in the product labeling. Exactly what this might be is not obvious to
the casual observer.
issue of exactly what performance targets and studies are required to capture an
abuse-deterrent claim will have an impact on the approval and claims of future products,
including generics. Regardless, products that include any sort of abuse-resistant
or deterrent features are a net benefit to the public whether or not they receive
the corresponding claims from the regulatory bodies.
– THE FUTURE
still in relative infancy, the whole area of abuse-deterring formulations is likely
to grow up very quickly, and likely without any privilege. It’s not unlike the mid-1990s,
where sustained-release formulations quickly became a standard part of every
company’s formulation toolbox. It was at this point no longer necessary to
secure external expertise to create a long-acting formulation of a proprietary
molecule. This point was emphasized by the parallel emergence of sustained-release
generic products in the mid to late 1990s.
It may be
that the golden age of abuse-deterrent formulation technologies has already
passed before it has had a chance to flourish. That’s not to suggest abuse-resistant
and deterrent formulations in the pipeline won’t be approved and provide important
therapeutic benefits. Rather, the opportunity to profit through market share and
pricing flexibility as a result of any significant technology or regulatory exclusivity
will be limited. The actives, for the most part multi-source opioids and stimulants,
provide no real patent exclusivity. And with the development of multiple
abuse-deterrent formulation strategies, there appears to be little potential for
any true exclusivity from a technology perspective. It is difficult to imagine
that any company will be able to capture the type of profit with abuse-deterrent
products or technologies as has been enjoyed by Purdue Pharma and their
hard to predict that we will see more and more abuse-resistant and deterrent
formulations of opioids and stimulants hit the market in the near future, followed
by their generic equivalents. The real money to be made will be found in those
products that change the whole paradigm – novel molecules that retain desired
analgesic or psychoactive properties but without any inherent addictive or
abuse-reinforcing properties. It’s possible these molecules will be discovered,
but it does not seem it will be anytime soon. In the meantime, patients,
physicians, and society as a whole will need to look to the ingenuity of
pharmaceutical science professionals to provide meaningful near-term solutions.
this issue and all back issues online, please visit www.drug-dev.com.
Josef Bossart is Managing Director of The Pharmanumbers Group, a boutique
research and consulting group providing the biopharmaceutical industry with
analysis and insights that improve business outcomes. He has more than 3
decades of experience in the biopharmaceutical sector, including senior sales, marketing,
business development, and management positions within Big Pharma, Specialty
Pharma, and Emerging Pharma companies. He earned his PhD in Medicinal Chemistry
from The Ohio State University, College of Pharmacy.
Tugrul T. Kararli earned his PhD in Pharmacology from the University of Florida and
his MBA from DePaul University. Dr. Kararli worked at Searle/Pharmacia for 18
years and held various positions and responsibilities within the Pharmaceutical
Sciences department, participating in pharmaceutics, product development, and
drug delivery activities. As the Chairman of the Global Drug Delivery Technology
Team at Pharmacia, he was responsible for identifying, planning, and executing the
drug delivery technology strategies for marketed and development products. Dr.
Kararli has authored numerous articles on various aspects of pharmaceutics and
drug delivery and holds more than a dozen US and international patents.
Currently, he is the Founder and President of PharmaCircle LLC, a knowledge
management service company in the drug delivery and pharmaceutical/biotechnology
Kurt Sedo is Vice President of Operations at PharmaCircle LLC. He earned his
BS in Chemistry and Mathematics from the University of Wisconsin Stevens Point.
Prior to joining PharmaCircle in 2003, he held various R&D Scientist positions
within Searle/Pharmacia’s Pharmaceutical Sciences Department in Analytical Development
and Drug Delivery.