Based on the nature of the diseases and rare conditions represented by these indications, most studies were case reports without comparator groups. Thus, there were several deficiencies in various clinical studies. However, some useful information on safety emerged from these studies.

Intravitreal injection of Kenalog suspensions was commonly investigated (Bitter et al. 2008). The studies on toxicity have been conducted using triamcinolone suspension. Although there was sparsity of data on the safety and efficacy, off-label use of intravitreal triamcinolone acetonide was often employed in the treatment of various posterior segment disorders. Elevated intraocular pressure and cataract progress are the most common occurring adverse events in 20–60% patients following the intravitreal injection. Other less frequent side effects occurring in almost 2% of patients include endophthalmitis, eye inflammation, vitreous floaters, injection site reactions (blurring, transient discomfort), detachment of retinal pigment epithelium, conjunctival hemorrhage, etc.

Irrespective of the therapeutic benefits of intravitreal triamcinolone acetonide injection, the most common unsolved problems associated with the injection procedure or vehicle are endophthalmitis and pseudoendophthalmitis. It was concluded in some studies that the toxicity can be associated with the ingredients of the vehicle. In particular, the preservative benzyl alcohol was implicated in the retinal toxicities of the Kenalog formulation. To overcome this, varoious formulations were prepared by the clinical pharmacies, employing a Kenalog wash protocol to remove benzyl alcohol. However, the residual benzyl alcohol content and the varying drug contents of the different suspension formulations could contribute to the differences in drug dosing, leading to complications in comparing the results from various clinical investigations. The clinical data with the FDA approved, preservative-free triamcinolone acetonide suspensions are currently accumulating. Cell culture studies are indicating that preservative benzyl alcohol-containing formulations are more cytotoxic than those free of benzyl alcohol; further, some studies are indicating that crystalline suspensions when in contact with cultured cells induce apoptotic cell death (Chang et al. 2006, 2007, 2008; Szurman et al. 2006; Kaczmarek et al. 2009). Once sufficient clinical knowledge accumulates regarding safety of intraocular triamcinolone acetonide suspensions, the same information can be potentially extrapolated to other suspensions intended for the back of the eye.

18.4  Conclusions

Administration of preformed or in situ forming drug suspensions offer a unique delivery advantage for the back of the eye in terms of their manufacturing simplicity and the feasibility of sustained drug delivery. After several years of off-label use of corticosteroid suspensions, preservative-free triamcinolone acetonide suspensions were recently approved for administration in the back of the eye. Intraocular suspensions­ should be sterile and preservative-free for maximum safety. Since suspension­ manufacturing is routine for parenteral dosage forms, some of the

knowledge from parenterals can be readily applied to ophthalmic suspensions. Data are currently equivocal regarding the safety of particles coming in contact with cell surfaces in the eye.

Acknowledgments  This work was supported by the NIH grants R01EY018940 and R01EY017533.

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Chapter 19

Regulatory Considerations in Product Development for Back of the Eye

Ashutosh A. Kulkarni

Abstract  This chapter strives to provide an understanding of the overall drug product approval process and highlights the key points that a sponsor needs to focus on in order to successfully develop and market a posterior ocular segment drug. Furthermore, the chapter reviews the product summary basis of approvals for two recently approved and marketed products namely Ozurdex™, a dexamethasone containing intraocular drug delivery system for the treatment of macular edema following branch or central retinal vein occlusion (BRVO or CRVO) and Lucentis™, a recombinant, humanized monoclonal IgG1 antibody antigen-binding fragment (Fab) indicated for neovascular (wet) age-related macular degeneration (ARMD). The importance of scientific dialogue between the sponsor and the corresponding health agency is emphasized and encouraged.

19.1  Introduction

An increasingly aging population around the world and specifically in the United States has led to an increased occurrence of a variety of ocular diseases that cause either ocular discomfort, debilitating visual impairment, or in some cases complete blindness. Some of the most common diseases among these include cataract, glaucoma, diabetic macular edema, and age-related macular degeneration (ARMD). The incidence and prevalence of these conditions have been reviewed by Clark and Yorio (2003). The prevalence of blindness is expected to significantly increase during the next decade (Ghodes et al. 2005). The pharmaceutical industry has taken note of this significant unmet need and is investing

A.A. Kulkarni (*)

Department of Pharmacokinetics and Drug Disposition, Allergan Inc, Irvine,

CA 92612, USA

e-mail: Kulkarni_Ashutosh@Allergan.com

U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye, 469 AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_19,

© American Association of Pharmaceutical Scientists, 2011

heavily in the development of safe and effective drug candidates for treatment of these diseases, including the treatment of posterior segment diseases. The drug candidates include vascular endothelial growth factor (VEGF) inhibitors, receptor tyrosine kinase (RTK) inhibitors, corticosteroids, growth hormone inhibitors, and others (e.g., integrin inhibitors, Sdf1/CXCR4 pathway inhibitors, nACh receptor antagonists, and pigment epithelium-derived factor gene therapy) (Marra et al. 2007).

In addition to developing safe and effective drug candidates, their delivery to the target tissues is also of critical importance. Drugs can be delivered to the eye following local or systemic administration. Local administration via the topical ocular route results in very low bioavailability limiting this route to mainly treat the diseases of the anterior chamber. This is mainly because the drug has to cross penetration barriers, is subject to rapid clearance from the tear film and has to travel against the intraocular fluid flow gradient (vitreous to aqueous) if administered topically. Scientists are still attempting to use this route but many attempts at using this route for drug delivery to the back of the eye have failed. For the posterior segment diseases such as ARMD, systemic administration, intravitreal injection or periocular administration provide feasible alternatives. However, systemic administration has its own set of challenges including the need to penetrate the blood-retinal barrier (BRB), avoiding any efflux transporters present on the retinal surface, and most importantly exposing the systemic circulation to high drug concentrations and the potential for systemic side effects. For this reason, systemic administration is not a favored route for treating diseases of the back of the eye. Intravitreal administration and periocular routes of administration are currently the most preferred routes for delivering the drugs to the back of the eye. The different anatomical locations for administration of a variety of drug delivery systems for posterior segment diseases are reviewed by Lee and Robinson (2009). Therefore, in addition to developing safe and effective drug candidates, it is important to devise innovative, minimally invasive techniques to deliver these drugs to the back of the eye so that they can effectively reach the target tissues, such as the retina, provide therapeutic concentrations at these target tissues and improve patient compliance. These issues have been discussed in detail in the earlier chapters of this book.

To date, regulatory guidance specifically geared towards the development of posterior segment therapies has not been issued. In addition, differences exist among the various health agencies worldwide and this need to be taken into account during development since most drugs are developed with the intent of marketing them worldwide, not just in the United States. Therefore it is very important to have a global development plan in place before embarking on the long and expensive journey of conducting preclinical and clinical studies to support market registration. The global development plan is an important document that provides a roadmap for executing the various phases of drug development in a well coordinated, timely, and effective manner. It is also critical that the pharmaceutical company (sponsor) work closely with the regulatory agencies to assure that the development program will meet the expectations and criterion set forth by the agencies.