Article Date: 3/1/2007

Untitled Document

UPFRONT
Focus Required in Clinical Trials



JASON S. SLAKTER, MD

Perhaps the biggest debate within the retinal community at the beginning of 2007 is whether bevacizumab (Avastin, Genentech) is as effective as ranibizumab (Lucentis, Genentech) in the treatment of exudative age-related macular degeneration (AMD). To date, most physicians have utilized bevacizumab for over 1 year, resorting to this off-label approach while awaiting Food and Drug Administration approval of ranibizumab in June 2006. During that time, we began forming our own opinions regarding the efficacy of bevacizumab for patients with different types of choroidal neovascularization (CNV), as well as the agent’s durability and safety. Peer-reviewed publications have appeared, ranging from small case series to reports of several hundred patients treated with bevacizumab, showing short-term efficacy and safety using this molecule.
While compelling, the bevacizumab data do not carry the same scientific weight as masked, controlled trials of ranibizumab, where 24-month vision data are available from 2 independent trials. In addition, a more rigorous protocol for collection of safety data in the ranibizumab trials leaves open the question of comparative safety of bevacizumab in the AMD population, particularly in light of a recent report of a mild safety signal from the SAILOR trial (see “Lucentis Stroke-risk Data,” page 12).
NEI TRIAL: BEVACIZUMAB VS RANIBIZUMAB

Last October, the National Eye Institute (NEI) announced plans for a head-to-head trial comparing these 2 molecules in an attempt to provide us with useful clinical data that would help to guide physicians in treating their patients. On the surface, this announcement was met with excitement and anticipation. However, as details of the trial have come forward, including the complexity and scope of the study, some issues have arisen.
Instead of a simple head-to-head comparison of monthly treatment with either bevacizumab or ranibizumab, the planned NEI trial design has multiple treatment arms and is designed to answer several questions at once, including how bevacizumab and ranibizumab compare for standard monthly dosing and what alternative dosing regimen can be used with retreatment based upon OCT and other criteria.
There are several difficulties that arise when a single study seeks to answer multiple questions. Complexities of trial design prolong the recruitment of the trial, increase costs, and, most importantly, delay the availability of study results. A simplified trial design conceivably could have been initiated as early as January of this year and would likely have recruited very quickly, offering the possibility of trial data becoming available some time in the latter part of 2008. With the more complex trial plan, which at this point has not even completed the organizational stage, it is unlikely that useful data will be available before late 2009 or even the beginning of 2010.
Hypothetically, if bevacizumab were to be found comparable to ranibizumab, more than $1 billion could have been saved by having this information available earlier by using a more simplified approach. Of course, if the opposite outcome were observed and ranibizumab proved to be a better drug, clinicians would know to offer this superior therapy to their patients. In addition, a simplified trial would permit larger numbers of patients to be included in the 2 treatment arms, providing more information on comparative safety of the 2 drugs.
WE NEED ANSWERS NOW
This more simplified approach does not rule out the possibility of also studying alternative treatment regimens in separate trials. However, it is important to keep our eyes focused on the primary goal of comparing these 2 drugs for treatment of CNV due to AMD, especially when other pharmacologic agents are on the horizon.
It is conceivable that 12-month pivotal data from other anti-vascular endothelial growth factor (VEGF) drugs, such as the VEGF-trap (Regeneron Pharmaceuticals) or the siRNA agents (Acuity Pharmaceuticals, Merck & Co.), could be available at the same time that the currently planned NEI trial is complete and the data presented.We could thus be faced with a new question: How do ranibizumab and bevacizumab compare with a new drug with a different dosing regimen and different safety profile? This would undoubtedly lead to a call from the retinal community for additional clinical studies comparing all of these agents, possibly leading to an unending series of trials where the data become available just at the time when it is least useful.
With this in mind, perhaps we should focus on answering the simple questions in a timely manner while exploring more detailed issues in separate trials.



Retinal Physician, Issue: March 2007