|Fig. 1. Extended-release formulation is rated as one of the most effective methods of extending the life cycle of a drug. Credit: Best Practices LLC|
The FDA clarified the regulatory thicket surrounding the 505(b)(2) approval pathway for drug formulations just over a decade ago. In the intervening years, this pathway has become an increasingly popular way for drug makers to commercialize products. The 505(b)(2) pathway allows companies to make modest changes to an already approved drug and get continued market exclusivity for from three to as many as seven years. And among those changes, one of the more popular is to develop a controlled-release, long-acting, extended-release, or XR version of the drug, all of which constitute a modified-release approach.
Some drugs, from their first launch, are formulated to provide a relatively steady dose to the patient over an extended period of time, either to provide more effective therapy or better patient acceptance. Transdermal patches or medical devices like infusion pumps can serve a similar purpose. Most often XR formulations show up because a company is attempting to extend the exclusivity of its proprietary product, a form of life-cycle management for the drug as it nears patent expiration (expiry).
The choice is not without some controversy. Over the years drug makers have been accused of artificially extending patent life with this stratagem, presumably because only a sketchy justification exists for the XR form. In the case of opioid pain products, XR forms of drugs have been subverted by drug abusers seeking an instant high. Most XR opioid products now operate under Risk Evaluation and Mitigation Strategies [REMS] restrictions to limit such abuse.
Officials making drug-abuse policy are anxiously watching the introduction of Zohydro, an extended-release hydrocodone that the FDA approved last fall, by Zogenix (San Diego). Meanwhile, Purdue Pharma (Stamford, CT) is entering Phase-III trials of its version of XR hydrocodone. Officials fear a repeat of the drug abuse that occurred when Oxycontin, an extended-release oxycodone, was introduced in the mid-1990s.
However, many valuable justifications for the XR form—including formulations for pediatric or geriatric patients—exist. “FDA approvals under 505(b)(2) have risen every year since 2003 because it offers a faster and less costly process that permits developers to minimize risk and still receive marketing exclusivity,” said Ken Phelps in a statement commemorating the 10-year anniversary of his Cincinnati firm, Camargo Pharmaceutical Services, which specializes in those regulatory approvals. “Today, more drugs are approved through 505(b)(2) than through traditional development.”
Time, cost, and value
A just-published study, surveying the experiences of 25 pharma companies and their approaches to life cycle management (LCM), gives a context to XR decisionmaking. The study’s authors, Best Practices, LLC (Chapel Hill, NC), benchmarked respondents’ experiences with and results from a variety of LCM strategies. These approaches range from fairly straightforward ones, such as adjusting pricing of the product as expiry approaches, to fairly complex ones, such as researching a new indication for the drug, which can require nearly the same effort as for initial approval.*
Among top-rated choices (Fig. 1), the extended-release reformulation was rated as the second-most effective—just nosed out by repricing the drug—and having the highest “highly effective” rating. The companies preferred this strategy despite the fact that respondents noted in other polling that the strategy is expensive—$10 million or more according to two-thirds of respondents—and that it was one of the strategies that took longest to apply, upwards of three years to implement. By comparison, repricing the product takes less than a year to execute.
Another benchmarking comparison, of barriers to use (Fig. 2), demonstrates that XR reformulating is one of the more expensive approaches but not as expensive as developing a new indication. Lower-cost options are not shown in the chart. Best Practices rated XR formulation as about as difficult as setting up the drug’s marketing in an emerging market.
The grand-total benchmark, as it were, compares the cost and difficulty of the LCM techniques to the value obtained. Here, Best Practices found that XR reformulation has one of the highest ROIs, 84%, which is on par with development of an authorized generic.
Some pharma companies have in-house expertise in modified-release techniques; alternatively, a wide variety of formulation and drug-delivery providers in-license the technology and/or provide manufacturing expertise. These companies include:
Provided a pharmaceutical company has established a pharmacokinetic rationale, a strategic path to an improved version of the original drug, experts recommend starting the development of the XR form for LCM as early as is possible. Companies often initiate such programs even before the regulatory agency has approved the original, immediate-release version of the product.
Bend Research often uses a combination of bioavailability-enhancing technologies with sustained-release technologies for LCM. W. Brett Caldwell, director of formulation science, says “Recently, our clients have brought us more problem statements earlier in development that require modified-release formulations, combined with bioavailability enhancement, to help progress efficacious drugs that might not be viable as immediate-release candidates. Modified release can help a drug stay in the therapeutic window. Companies are much more savvy about optimizing the therapeutic window and are optimizing earlier in development.”
Caldwell indicates that the modification of a crystalline, immediate-release formulation into a sustained-release formulation is the most commonly considered method for LCM. He also sees increasing interest from clients in creating combination drugs, improving bioavailability, enabling new indications, and/or targeting specific populations through XR technologies. For example, moving from a tablet formulation to multiparticulates can help a pediatric or geriatric population by improving the ease of swallowing and avoiding the risk of dose dumping in the stomach. Developers can also design capsules that open and deliver the dose in milk or other foods.
Customers of Metrics usually tell them up front that they want a modified-release formulation. The company seldom includes XR approaches as an initial formulation strategy, unless pre-formulation work reveals that modification of the release is necessary. Joe Cobb, director of pharmaceutical development, indicates that the drug load in the immediate-release dosage form must be relatively low to consider using an XR profile as a tool for LCM.
Robert Lee, VP of pharmaceutical development services at Particle Sciences, believes that sustained release must give you something of value and add to the biological efficacy of the drug. For LCM, the new formulation has to improve upon the innovator’s product. He says, “Look at the pharmacokinetic profile of the current product and ask if sustained release adds therapeutic value. In some cases, you don’t want sustained release. It boils down to deficiencies in the original formulation. If the problem is poor oral bioavailability or variable food effects and Cmax is not necessarily of concern, then you don’t want sustained release.”
Lee indicates that most companies wait until just before the patent expires to launch a new dosage form. He suggests that they might want to launch earlier because they could gain a larger or retain market share. Lee indicates that companies should start development at least two or three years before a patent expires to be sure the new formulation can show differentiated, improved performance through the studies that are required to get regulatory approval. Lee also indicates that companies should review possible competitors for a specific API. Instead of another generation of the API, a sustained-release drug combination using two compounds or a drug-device combination, such as a sustained-release dispenser pump that marries a drug to a device, may be a better idea.
Patheon uses XR technologies mostly for LCM, with the exception of drugs requiring targeted delivery. Immediate-release dosage forms are a conventional strategy pursued by the company; however, XR is a strategy that it uses for LCM to obtain maximum therapeutic value for a drug. Anil Kane, executive director of global formulation sciences, says that clinical benefits and a need to protect intellectual property are the criteria that suggest use of sustained-release over other LCM strategies, such as development of fixed-dose combinations or pediatric drugs. He suggests that companies should begin development of the new formulation around Phase III of successful clinical trials for the original product because its development will require long clinical trials and safety studies.
Shikha Barman, president of Integral BioSystems, says that the development timeline of an improved XR formulation should anticipate its market introduction at least a year prior to the original patent expiring to ensure continuity of revenues.
|Fig. 3. An example of “osmotic swellable core” release modification. Credit: Capsugel|
Methods of drug delivery
CDMOs and CROs develop modified-release drugs for clients that use a wide variety of drug-delivery technologies. In addition to the common oral delivery systems, recent examples also include products that: (1) are insertable; i.e., implants; (2) are erodable, such as suppositories; (3) are injectables, with depots that deliver over time; (4) are inhalable powders; or (5) are ocular or transdermal delivery systems.
Some companies focus entirely or primarily on oral dosage forms. Metrics develops solid, oral dosage forms exclusively because these forms have enjoyed the greatest amount of research and they provide the most options for modified-release delivery systems. Patheon primarily develops products that use oral or sterile drug delivery.
Bend Research typically doesn’t feel constrained by delivery route or therapeutic area, basing development on collaboration with its clients on formulation design, often using pharmacokinetic models. Its clients, however, typically prefer the oral delivery route using either tablets or capsules. The company examines hypothetical profiles that are deliverable using its technologies and hones in on lead technologies for initial studies. Caldwell says, “This approach is efficient and can be achieved rapidly with little-to-no empirical testing and without significant API usage.”
Particle Sciences also uses a variety of drug-delivery systems based on the scientific requirements of a drug, and it develops modified-release formulations for drugs that have issues with bioavailability and with control of some aspect of release. For example, for vaginal HIV prevention or contraception, the indication supports use of intravaginal rings that provide sustained release.
Customers of Integral BioSystems mostly are small and virtual companies, with proprietary drugs or repurposed drugs that use ophthalmic, transdermal, and injectable routes. In addition to these technologies, the company has developed two of its own proprietary, sustained-release ophthalmological delivery systems: EySite, for both front-of-the-eye and back-of-the-eye indications such as age-related macular degeneration, diabetic retinopathy and diabetic edema and Ocusurs, for delivery of drugs to the ocular surface.
CDMOs and CROs believe that the regulatory environment won’t affect use of modified-release technologies. Brad Gold, VP of pharmaceutical development at Metrics, says, “Scrutiny by regulatory agencies, such as the FDA or the European Medicines Agency, regarding modified-release dosage forms has always been higher than for immediate-release counterparts. The scrutiny arises because modified-release dosage forms typically have more of the API than the immediate-release products do.”
Caldwell at Bend Research says that regulatory requirements are increasingly dictating abuse-deterrence mechanisms for certain drug classes. Opioids, combination opioids, and other drugs are often formulated for extended release, and abusers are manipulating these drugs to get an immediate high. Multiple approaches to formulation involving use of waxy excipients, gelling agents, and taste modifiers are increasingly being used to deter abuse while achieving the needed extended-release dissolution profiles.
Barman at Integral BioSystems says, “The FDA actually encourages companies to request guidance when creating drugs that use MR technologies. The agency has recognized the medical and other benefits of such systems.”
Whether to manage a product’s life cycle or to address the bioavailability profile of a new drug, modified-release techniques will get a closer look as pharma companies pursue more specialized conditions and diseases.
Caldwell at Bend Research sees multiple therapeutic areas related to chronic conditions that can use modified release, including treatment of cardiovascular disease, high blood pressure, diseases of the central nervous system (CNS) and depression, attention-deficit hyperactivity disorder (ADHD), diabetes, and urinary incontinence. In addition to chronic conditions, he sees continued growth for pulsed or sustained release to help in acute areas, such as antibacterials where ideally drugs are delivered locally, and perhaps, without absorption. Also, pulsatile technologies can be helpful for drugs for which developers don’t want constant blood concentrations, such as to avoid tolerance buildup for opioids.
Lee at Particle Sciences says that therapeutic areas that require drug delivery over an extended period of time are good candidates for sustained release, particularly for areas where patient compliance or other factors like drug abuse are an issue. Use of sustained release in drugs treating Alzheimer’s disease or providing contraception or HIV prevention can increase patient compliance. Treatment of constant pain and oncology are also good candidates. For oncology, sustained release can provide the highest dose that will kill a cancer and not damage tissue. For Parkinson’s or other CNS disorders with symptoms that require control long-term, sustained release is also a good solution.
Barman at Integral BioSystems also believes that sustained release provides opportunities for treatment of urological conditions. She says that menopausal women often have repeated urinary tract infections, and local delivery of a sustained-release antibiotic could allow a drug to focus on the involved cells in the body and tackle bacteria in the bladder and urethra over an extended period to prevent the recurring infections.
Generally, the experts believe that the future is good for modified-release technologies, given that their use can provide a clinical benefit and that the science behind the drugs supports use of modified release. The challenges around efficacy and LCM make growth likely. The lack of new pharmaceutical compounds in the discovery phase of drug development makes LCM very important, and MR dosage forms should become an important strategy in extending the life of established, high-revenue drugs.