By Eric K. Steffe, Bonnie Nannenga-Combs, Ph.D., and Gaby L. Longsworth, Ph.D.
Sizable revenue is generated through exclusive rights to market branded drugs. Thus, patent expiry and the end of data exclusivity are major concerns. Reformulating the active ingredient of existing drugs such that approval by the Food and Drug Administration (FDA) is required prior to commercialization is one way to secure additional data exclusivity periods. If patients are migrated to a new patent-protected formulation, additional exclusivity periods and patents covering reformulations can have significant commercial value.
Reformulation Strategies For Small Molecules
Strategically, a successful “reformulation” involves altering the characteristics of a drug just enough to obtain additional patent protection, while keeping enough characteristics the same so that previous clinical testing results can be relied on to obtain FDA approval. Upon receiving approval for the reformulated product, marketing of the old formulation can be discontinued. Nothing prevents a New Drug Application (NDA) holder from unilaterally discontinuing a listed drug. Discontinued drugs are no longer available as a Reference Listed Drug for ANDA filers. Under current FDA regulations, an ANDA applicant cannot reference an NDA once it is removed from the Orange Book.
Using this strategy, new patent(s) covering a reformulated product can be listed in the Orange Book under either the existing brand or a new brand, and the drug can be promoted as improved in some way. If successful, a company may be able to retain market exclusivity, which would have been lost to generic competition upon expiration of patent protection for the original formulation.
Data Exclusivity For Small Molecules
Data exclusivities can be obtained for a newly formulated drug, including new dosage form or new use exclusivity, which prevents the FDA from approving an ANDA for three years from approval of the newly formulated product. Orphan drug exclusivity (ODE) and pediatric exclusivity also remain available. ODE prevents the FDA from approving an ANDA until seven years from approval of the newly formulated product. Pediatric exclusivity extends all FDA market exclusivities by six months, e.g., five year new chemical entity (NCE) exclusivity, four year NCE-1 bar to ANDA filing, three year new formulation exclusivity, and seven year ODE. In addition, pediatric exclusivity effectively extends the term of all Orange Book listed patents by six months. This additional six months, which is cumulative to all other patent extensions, is a regulatory exclusivity. Thus, it will prevent approval of an ANDA, but not provide any other independent patent rights.
Routes Of Administration For Small Molecules And Reformulation Options
Improvements to existing drugs typically include (a) reformulating the molecular entity (ME), (b) the manner of delivery, or (c) switching to a new indication. Examples of molecular entity reformulations include metabolites (e.g., Claritin ► Clarinex), enantiomers (e.g., Prilosec ► Nexium), and polymorphs (e.g., Paxil).
A new manner of delivery can include changing the drug dosage form or changing the route of administration of the drug. For example, Warner Chilcott’s Ovcon was changed from an oral tablet to a new patent-protected chewable tablet with the identical active ingredients.
Another example is TriCor (fenofibrate), which was first approved in capsule form. It was then approved in a micronized tablet formulation, and finally a new nanoparticulate tablet dosage formulation.
Another way to reformulate is by changing the route of administration to create a pharmaceutically different drug product. Although a new NDA must be filed, if the drug is bioequivalent to a previously approved drug, the drug company can avoid most of the time and expense associated with clinical testing. For example, desmopressin acetate was first approved by the FDA for the treatment of diabetes insipidus and later as a treatment for bedwetting. The original patent taught that the drug could be administered to the patient through “peroral” and other applications, whereas a later filed patent claims that the drug can be administered through absorption in the gastrointestinal tract.
Switching to a “new indication” involves obtaining approval and patent protection for a new method of use for an existing drug. However, to completely block generic competition for the new indication, the drug company must file an NDA and list the new method of use patent in the Orange Book, which sometimes is cost-prohibitive.
Reformulation Strategies For Biological Products
Biologics are becoming more prevalent in the market. There are currently more than 150 Biologic License Applications (BLAs) approved in the U.S. The manufacturing processes for biologics are different than for small molecules. Biologics are usually manufactured in living systems that produce similar, but not necessarily identical, products. Structural alterations (e.g., changes in glycosylation) or system contaminants can lead to immunogenicity issues not associated with the original product. Product differences may even be present within the same batch. Thus, there are both opportunities and challenges for companies interested in reformulating biological products.
Under the Biologics Price Competition and Innovation Act (BPCIA), a product can be a “biosimilar” if there are no clinically meaningful differences (in terms of safety, purity, and potency) as compared to the reference product. Additionally, biosimilar approval will only be granted for a previously approved indication and condition of use. To be “interchangeable,” the product must achieve the same clinical result as the reference product in any given patient. Similarly, if administered more than once, the risk of alternating between the biosimilar and the reference product can be no greater than the risk of maintaining the patient on the reference product. Interchangeable, but not biosimilar, products may be substituted for the reference product by a pharmacist without a prescription.
While minor changes to the formulation and/or delivery device are allowed if they do not introduce clinically meaningful differences, the FDA will only approve a biosimilar if its mechanism of action, route of administration, dosage form, and strength are the same as the reference product.
Data Exclusivity For Biologics
New biologics receive 12 years of data exclusivity. However, the FDA will accept a 351(k) biosimilar filing 4 years after the first biologic product is licensed. According to the FDA’s draft Guidance published August 2014, an additional 12 years of exclusivity will not be granted for new indications, routes of administration, dosing schedules, or dosage forms. A new period of exclusivity will only be granted if changes are made to the structure of the biological product that alter safety, purity, or potency.
Under 42 U.S.C. § 262(m), granted pediatric exclusivity will extend by six months (a) the 12 year data exclusivity period barring the approval of a biosimilar application for the product, (b) the 4 year period barring the filing of a biosimilar application for the product, and (c) any ODE. Similar to small molecules, biologics can get pediatric exclusivity that attaches to data exclusivity periods.
Unlike the FDA's Orange Book for small molecules, the Purple Book for biologics contains no patent information. Instead, it merely lists approved biologics, biosimilars, and interchangables.
Routes Of Administration For Biologics And Reformulation Options
Most biologics are administered through parenteral routes (e.g., intravenous infusion and subcutaneous or intramuscular injection). Biologics are commonly administered by IV infusion because of the need to, e.g., deliver safe concentrations, maintain stability, avoid aggregation and undesirable viscosity properties, and limit degradation in the digestive tract due to short half-life.
Biologics can be difficult to formulate for subcutaneous or intramuscular delivery as these typically involve injection of small volumes of highly concentrated drug solutions. Biologics that need to be given in high doses and/or have limited solubility can be particularly challenging and lead to loss of biological properties., Changes to the route of administration can also impact the dose and dose frequency, e.g., small volume subcutaneous or intramuscular injections of a biologic will likely need to be administered more frequently and/or at a higher dose compared to the same dose administered by infusion.
One example of strategically reformulating a biologic is the transition of Hoffmann-La Roche's Herceptin (trastuzumab) IV infusion formulation to a subcutaneous formulation. The transition coincided with the expiration of Roche’s first European patent in 2014 (U.S. expiration is due in 2019). In 2013, a new subcutaneous formulation of Herceptin was approved in Europe for the treatment of HER2-positive breast cancer. Herceptin was originally administered to patients intravenously for 30 to 90 minutes per dose. In contrast, the subcutaneous formulation of Herceptin can be administered in two to five minutes subcutaneously. In the U.S., a Phase 3 study is recruiting patients to evaluate the safety and tolerability of Herceptin administered subcutaneously by a single-use injection device in patients with HER2-positive early breast cancer. There is currently no approved Herceptin biosimilar in the U.S., but Pfizer is working on one (PF-05280014).
Roche is also attempting a biosimilar reformulation for Rituxan (rituximab), which was also approved in 2014 in Europe. Rituxan’s European patents expired in 2013 and are due to expire in the U.S. in 2016. It remains to be seen whether Roche’s reformulation strategy will allow it to retain a significant portion of the Herceptin and Rituxan markets in the face of likely biosimilar competition.
There are a number of non-injection technologies being developed in collaboration with companies specializing in alternative formulation and delivery strategies (e.g., oral delivery systems (Emisphere Technologies), transdermal microneedles and patches (3M Drug Delivery Systems), and pulmonary delivery (Aradigm Corporation)). For example, Novo Nordisk is currently developing oral formulations of GLP-1 receptor agonists and insulin using Emisphere's technology.
Some reformulation strategies have encountered skepticism and even failure. Pfizer abandoned its attempt to move the diabetes market from injected insulin to its inhaled insulin product, Exubera, in 2007. Despite regulatory approval in 2006, the inhaled insulin failed to gain market share, and after only a year of sales, Pfizer was left with an estimated loss of at least $2.8 billion when it withdrew Exubera from the market. Despite the failure of Exubera, MannKind Corporation sought and obtained approval in 2014 for Afrezza, a rapid-acting inhaled recombinant human insulin. As of October 2015, Afrezza sales were well below MannKind’s target range. Time will tell whether the market will eventually move toward inhaled non-injection insulin product for diabetes patients.
Another strategy to migrate the market toward more effective biologics includes making changes to the active agent, e.g., modifying the active agent (such as by pegylation) or administering DNA or mRNA-encoding a known active agent. Depending on the changes made and whether the changes result in altered safety, purity, or potency, some of these products might be eligible for approval as new active agents, which would provide for a new exclusivity period, as well as any new patent term that might be obtained.
Amgen extended its dominance in the market for almost two additional years after the patent to Neupogen (filgrastim) expired in the U.S. in December 2013. Amgen manufactures Neulasta (pegfilgrastim), a PEGylated recombinant methionyl human GC-SF for severe cancer chemotherapy-induced neutropenia. Pegylation can improve physical properties of the molecule, such as solubility, thermal stability, and immunogenicity. Pegfilgrastim has a human half-life of 15 to 80 hours (much longer than the parent Neupogen (filgrastim) (3 to 4 hours)), allowing for a single dose administration per chemotherapy cycle.
The approval of Zarxio (filgrastim-sndz), a biosimilar to Neupogen (filgrastim), introduces another option for health care professionals. However, it seems unlikely that patients who switched to single dose pegfilgrastim will go back to multi-dose filgrastim.
Compared to small molecules, opportunities to migrate the market for biologics are not as prevalent. That said, companies are developing strategies for reformulating biologics with varying success.
- CENTER FOR DRUG EVALUATION AND RESEARCH, U.S. FOOD & DRUG ADMIN., APPROVED DRUG PRODUCTS WITH THERAPEUTIC EQUIVALENCE (2007) (commonly known as the Orange Book).
- Licensed Biological Products with Supporting Documents. http://www.fda.gov/BiologicsBloodVaccines/ucm133705.htm. Accessed March 7, 2016.
- Section 351(k)(7) of the Public Health Service Act.
- Draft Guidance for Industry on Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the Public Health Service Act; Federal Register: Volume 79, Number 150 (August 5, 2014), pages 45448-45450. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM407844.pdf. Accessed March 7, 2016.
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