Generic drugs for the treatment of ocular conditions: changing the treatment landscape

Abstract

As global spending on medicinal products continues to rise, the availability of lower-cost generic substitutes is increasingly driving health care decision-making. US FDA does not require strict demonstration of human bioequivalence and/or therapeutic studies for the approval of generic ophthalmic compounds. Bioequivalence between generic and innovator compounds is presumed on the basis of matching active and inactive ingredient profiles. Generic compounds may differ from innovator agents with regards to performance under environmental stress, relative acidity and bottle size/rigidity. Matching ingredient profiles may therefore not result in consistently comparable drug compositions and clinical effects.

Keywords::

• generics
• glaucoma
• intraocular pressure
• ocular
• ophthalmology
• pharmaceuticals

Global spending on medicinal products is expected to reach 1 trillion dollars this year and is forecasted to grow to 1.2 trillion dollars by the year 2017 [1]. Although reaching a 1 trillion dollar threshold represents a sizeable overall pharmaceutical market, it is important to realize that overall projected growth over the next 5 years will occur at a relatively low rate. This low rate of growth is attributed to ‘blockbuster’ drug patent expiries and the increased use of generic alternatives. Indeed, the availability lower-cost generics are increasingly driving health care decision-making as the Japanese government will mandate 60% of all prescribed off-patent drugs to be dispensed as generics by the year 2018 [2].

US FDA regulates the approval process for generic agents within the USA. For the purposes of this article, discussion of generic agents will be limited to topical solutions approved after 1992. The history of US drug regulations prior to 1992 are nicely discussed in an article by Cantor [3]. Potential differences in the composition and efficacy of topical suspensions are accepted, and therefore similar agents in the same drug class are not deemed to be generic substitutes [4,5]. Indeed, the FDA requires separate clinical efficacy studies for ophthalmic suspensions, gels, emulsions and other nonsolution topical compounds as well as reformulations as it is well recognized that the composition of these compounds is significantly affected by manufacturing processes. The FDA Office of Generic Drugs recently issued draft guidance with regard to strict clinical study design requirements for the investigation of clinical efficacy of generic versus innovator brinzolamide (a suspension) and generic versus innovator cyclosporine (an emulsion) [6,7]. The drug approval process was changed in 1992 after the introduction of the Generic Drug Enforcement Act required generic substitutes to contain the same active and inactive ingredients as the innovator agent. An important consideration for generic ophthalmic agents, as compared to systemic agents, is that the FDA does not require strict demonstration of human bioequivalence and pharmacokinetic assays as this would require invasive ocular procedures [3]. Bioequivalence is presumed on the basis of a matching ingredient profile between generic and innovator drugs. Similarly, studies demonstrating therapeutic equivalence between generic and innovator solutions are also not required [5]. So, although generic compounds must have an identical chemistry when compared to innovator products, the FDA does not require tests of pharmacokinetics, therapeutic efficacy, and therapeutic safety. Ophthalmic generic compounds, however, must be identical in strength, dosage form, route of administration, have the same indications/contraindications, and abide by the same Good Manufacturing Practices standards as innovator agents [8].

The lack of strict requirements for bioequivalence and/or therapeutic equivalency studies has sparked concern by the ophthalmic community over the growing use of generic agents. Matching active and inactive ingredient profiles within generic and innovator ophthalmic solutions may not result in consistently comparable drug compositions and clinical effects. Using liquid chromatography–tandem mass spectrometry, Kahook and colleagues investigated changes in the concentrations of active and preservative ingredients in brand name latanoprost and dorzolamide-timolol compared to their respective generic compounds at baseline as well as at 25 and 50°C conditions after 30 days [9]. The group found that generic latanoprost products contained active ingredients greater than 10% of their labeled value, and this concentration decreased significantly at 25 and 50°C conditions after 30 days. Similar variances from labeled concentration and changes with environmental condition were not found for the brand name products. Micro-imaging revealed a greater quantity of particulate matter in the generic versus the brand name products. These differences in drug concentration and particulate matter presence were not directly translated to clinical effects; however, they do speak to the potential inadequacy of matched ingredient profiles to account for all potential differences between generic and innovator compounds.

A critically important attribute of ophthalmic medicines, not directly studied in FDA applications for approval of a generic compound, is medication bottle material and design. The FDA currently does not require formal comparative studies of bottle compositions and designs for generic drug applications. Differences in bottle size and rigidity are known to affect patient compliance, which may often impede achievement of therapeutic targets [10]. Indeed, in a study investigating barriers to compliant therapy, patients cited difficulty with squeezing the bottle as a major barrier to adherence with their prescribed regimen [11]. Further study revealed a wide variety in force requirements, as measured by a static pressure transducer, of different commonly used ophthalmic agents [12]. Potentially differing bottle designs further raises the concern for variable compliance issues and subsequent clinical effects in generic and innovator ophthalmic products.

Few published studies have compared clinical therapeutic effects of innovator and generic topical ophthalmic solutions approved by the FDA after 1992. Narayanaswamy et al. compared the clinical efficacy and safety of innovator drug, Xalatan (Pfizer Ophthalmics), and generic substitute, Latanoprost (Latoprost, Sun Pharmaceuticals, India), in a single-center, randomized, 24-week, observer-masked, crossover study [13]. Thirty subjects were randomized to initial treatment with either Xalatan or Latoprost for 12 weeks and then crossed-over to receive the comparative treatment for 12 additional weeks. Mean baseline intraocular pressure (IOP) was similar (23.64 ± 3.13 vs 22.74 ± 2.57 mm Hg, p = 0.399) between the groups initially treated with Xalatan and Latoprost, respectively. However, by week 12, the group initially treated with Xalatan had experienced significantly greater IOP reduction compared to the group initially treated with Latoprost (14.29 ± 1.61 vs 16.98 ± 2.49 mm Hg, respectively; p < 0.001). After cross-over, the group subsequently treated with Xalatan demonstrated further IOP reduction while the group subsequently treated with Latoprost experienced an increase in IOP. A greater percentage of subjects initially treated with Xalatan experienced IOP reduction greater than 30% from baseline at 12 weeks compared to subjects initially treated with Latoprost. The study found no significant difference in the rates of adverse events and/or conjunctival hyperemia between the two treatment groups. Although the generic agent comparator in this trial is manufactured in India, it is important to note that similar agents also manufactured in India have started to become available to patients worldwide as innovator substitutes. Egan and colleagues also performed a cross-over study investigating therapeutic effects of Xalatan versus generic latanoprost (Latalux, Sanitas, AB, Lithuania) in 35 patients with open-angle glaucoma [14]. All subjects underwent 4 weeks of therapy with Xalatan followed by a 4-week treatment regimen with Latalux. IOP was measured at four time points at baseline, at 4 weeks and at 8 weeks after enrollment. The investigators found no significant difference (p > 0.05) in time-matched IOPs measured at these three visits. However, a greater number of subjects achieved an IOP less than 14 mm Hg with Xalatan compared to generic Latanoprost (p = 0.013). Drug tolerability was found to be similar with each agent. It is important to note that each of these studies compared the clinical effects of an innovator agent to a single generic agent. In clinical practice, patients may be treated with a variety of generic agents, produced by different manufacturers, during a course of therapy.

The treatment of ophthalmic disease is often complicated by individually differing responses and adherence rates to identical therapies, potentially resulting in variable outcomes [15]. To make matters more elaborate, standard measurements of therapeutic response, such as IOP-lowering, are subject to relative imprecision and poor visit-to-visit repeatability [16]. The few published studies to date suggest that the growing availability of generic substitutes may add another variable to clinical response that may require awareness by the treating physician. With a number of clinical trials underway, the body of literature in this arena will surely grow to allow for a more enhanced understanding of comparative therapeutic efficacy between generic and innovator compounds.

Financial & competing interests disclosure

The author discloses speaker honoraria from Alcon Laboratories, Inc. and research support: from Akorn pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.