should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

The BLA application for LUCENTIS™ contained clinical data from seven trials that investigated the pharmacokinetics and pharmacodynamics of ranibizumab in humans at doses ranging from 0.05 to 2 mg. All clinical trials were conducted using a bolus Intravitreal injection of the drug product in patients with neovascular ARMD. The primary endpoint was proportion of subjects losing < 15 letters of visual acuity and the secondary endpoints were the proportion of subjects gaining ³ 15 letters of visual acuity at 12 months, the mean change from baseline over time in visual acuity score, and the proportion of subjects with a Snellen equivalent visual acuity of 20/200 or worse. Clinically meaningful and statistically significant benefits were seen in the primary endpoint at both 0.3 and 0.5 mg doses administered intravitreal over 12 months. Both doses were equally effective and showed a substantial benefit compared to control with the 0.5 mg dose providing a slightly better outcome in the proportion of subject gaining ³ 15 letters and the mean change in visual acuity score from baseline at 12 months. The ocular safety profile was favorable and key serious ocular adverse events appeared to be related largely to conjunctival anesthetic and intravitreal injection procedures. Following the BLA application, LUCENTIS™ was approved in June 2006.

19.7  Summary

To date, regulatory guidance specifically geared towards the development of posterior segment therapies has not been issued. However, a good understanding of the standard drug product approval process, the various regulatory guidelines, and specific ocular nonclinical and clinical programs provides a blueprint for success. Furthermore, a review of the summary basis of approvals (SBAs) for products that have been evaluated and approved by the FDA and/or other health agencies around the world is also helpful in comprehending the nature of these drug development programs. In addition, it is crucial that the sponsor interacts with the health authorities throughout the course of the drug development program to ensure that the program is on the right track for success. As we develop new and improved drug candidates for the treatment of various posterior ocular segment diseases with the help of cutting edge science, it is of utmost importance that we do so within the confines of each country’s ethics and regulation, and with the ultimate goal of improving patient health and quality of life, in sight.

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Chapter 20

Clinical Endpoints for Back of the Eye Diseases

Karl G. Csaky

Abstract  The development of new drugs and drug delivery devices for the treatment of posterior eye diseases is critically dependent on the potential for that drug to be approved by the United States Food and Drug Administration (FDA). This approval process is predicated on the successful achievement of endpoints in large multicenter clinical trials. This chapter will discuss the history and evolving nature of endpoints for these clinical trials. Updates on recent novel endpoints will be discussed as well as the potential for the use of readouts from various imaging tools of the retina as FDA acceptable endpoints for clinical trials.

20.1  Background

For any new drug to marketed and sold in the United States, it must undergo extensive testing in clinical trials and ultimately be approved by the FDA. The FDA approves drugs based on adequate information that demonstrates both the drug’s efficacy and safety. While this authority derives from the Federal Food Drug and Cosmetic Act this law allows a large amount of discretionary power to the FDA to determine what standards a drug needs to meet for adequate safety and efficacy. While the FDA has established many standards for both these outcomes, the evolution of medicine requires that many of these standards be continually reviewed and potentially updated. As will be noted below as new drugs for the treatment of retinal diseases are evaluated, approved and brought into clinical practice newer guidelines for approvability of a novel therapeutic evolve as well. This point as it pertains to therapeutics for retinal diseases will be discussed in this chapter.

K.G. Csaky (*)

Sybil Harrington Molecular Laboratory, Retina Foundation of the Southwest, 9900 N. Central Expressway, Suite 400, Dallas, TX 75231, USA

e-mail: kcsaky@retinafoundation.org

U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye, 485 AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_20,

© American Association of Pharmaceutical Scientists, 2011

The rate of development over the last 10 years of multiple therapies for retinal diseases has been enormous. In contrast until the year 2000 therapies for the vast majority of retinal diseases were limited to either retinal or cryo-destructive procedures. While the approach using two modalities of treatment appeared restrictive, the treatments were also recommended for use based on sound clinical trial data. For example, laser therapy had been demonstrated in elegant multicenter randomized clinical trials to be beneficial for diabetic proliferative retinopathy (1979), diabetic macular edema (1985), retinal neovascularization and macular edema associated with branch retinal vein occlusion (Finkelstein 1986) and choroidal neovascularization occurring in the setting of age-related macular degeneration (1991). In addition, cryotherapy had been demonstrated to prevent long-term vision loss in premature infants developing retinopathy of prematurity (1990). Interestingly, all of the above clinical trials were supported by the National Institutes of Health and utilized an approved medical device, laser photocoagulation, or cryotherapy. As such, additional FDA approval was not required to allow laser or cryo-therapy to be used in the above diseases.

20.2  FDA Endpoints

This background is important to understand the role that the FDA played in the development of therapies for retinal diseases. The concept of FDA approval was not part of the retinal lexicon until the advent of photodynamic therapy. However the numerous clinical trials that were undertaken prior to 2000 did set the stage for the requirements that were subsequently embraced by the FDA for drug approval for the treatment of retinal diseases. For example, the use of the binary outcome of the percentage of patients with a worsening of 15 or more letters was used as an endpoint for the approval of verteporfin for neovascular age-related macular degeneration (1999) primarily based on the fact that 15 letters represents a doubling of the visual angle using ETDRS visual acuity testing. The ETDRS chart consisted of fiveletter lines that have a geometric progression from line to line with every third line representing a doubling of the size of the letters. The ETDRS chart was developed for the Early Treatment and Diabetic Retinopathy study (Beck et al. 2007).

20.3  Endpoints for Neovascular Age-Related Macular Degeneration (Table 20.1)

The clinical trial for evaluation of the efficacy of verteporfin in neovascular AMD completed in 2000 was termed the TAP trial (Treatment of Age-Related Macular Degeneration with Verteporfin Therapy) and demonstrated that 61% of verteporfintreated eyes compared to 46% of placebo-treated eyes had lost fewer than 15 letters