CATT Study Update 8: The Story Behind The CATT Study
As any of you who have read this Journal know, I began writing about Avastin on January 31, 2006, after starting this online Journal the month before. I had read the first reports about this new drug in a report from the Retina Society Meeting held in July 2005, and then the first reports out of that year’s AAO Meeting. You can read my comments in my writeup, Avastin: A New Hope for Treating AMD.
Since that time I have written about Avastin vs. Lucentis 24 additional times, and about the CATT Study a previous 7 times. When I inquired earlier this month about the status of the CATT Study, Maureen Maguire was kind enough to send me a copy of the article she and Drs. Martin and Fine had submitted to Retina Times for publication in its Fall 2008 issue. I requested permission from both the editor of Retina Times and the three authors to reprint their story in my Journal to allow for wider publication than just the membership of the American Society of Retina Specialists (ASRS). I thank all involved for their cooperation in this effort.
Re-printed with permission of the authors and the American Society of Retina Specialists (ASRS). This article appears in the Fall 2008 Issue of Retina Times, the official publication of the ASRS, and is accessible by members only. For information about the ASRS, please go to www.asrs.org.
Comparison of AMD Treatments Trials (CATT): Lucentis – Avastin Trial
Daniel F. Martin MD, Maureen G. Maguire PhD, and Stuart L Fine MD
Drs. Daniel Martin (Emory University) and Stuart Fine (University of Pennsylvania) are Co-Study Chairs for the CATT Study, while Dr. Maureen Maguire (Director of the Coordinating Center at University of Pennsylvania) is the CATT Study Director.
Published in the Fall 2008 issue of Retina Times
Just over 3 years ago, two major events dramatically transformed the treatment of choroidal neovascularization (CNV) due to age-related macular degeneration (AMD). On July 17, 2005, the results of the MARINA trial comparing ranibizumab (Lucentis®) to placebo for the treatment of minimally classic and occult CNV were presented at the annual meeting of American Society of Retina Specialists meeting in Montreal. Patients assigned to ranibizumab were not only much more likely to maintain visual acuity (VA), but also had improvement in VA in unprecedented numbers. A few moments later, Philip Rosenfeld, MD, PhD presented a paper on the beneficial short-term effect of intravitreal injection of bevacizumab (Avastin®) in a single patient with neovascular AMD.
These events set off an explosion of controversy and debate on topics ranging from the penetration of molecules of different molecular weights through the retina to the ethics of off-label use of an untested agent when a well-studied, highly efficacious, and relatively safe drug was available, albeit at a very high price. By June 30, 2006 when the Food and Drug Administration approved ranibizumab for treatment of neovascular AMD, the data from additional Genentech randomized trials had provided strong evidence that ranibizumab’s efficacy and safety extended to a wide spectrum of neovascular lesions. In addition, substantial information on the pharmacokinetics, safety, and changes in vision after treatment with bevacizumab had accumulated, and the use of bevacizumab had become fully entrenched in many vitreoretinal practices.
The time was ripe for a head-to-head comparison to establish the relative efficacy and safety of these two drugs and to determine whether treating less than monthly with either drug could provide the same beneficial results on vision as the monthly injections. Led by investigators at Emory, University of Pennsylvania, and Duke, grant applications were submitted in January 2006 and received expedited peer review. In October 2006, the National Eye Institute approved funding for the Comparison of AMD Treatments Trials (CATT) – Lucentis-Avastin Trial.
Once funded, the major task that remained was to secure funding for the cost of ranibizumab and bevacizumab. The NEI grant covered the cost of purchasing, repackaging, and distributing Avastin. However, the $25 million drug cost for ranibizumab was not covered. This was anticipated and the CATT leadership had begun discussions with CMS early in the development of the trial design. The Centers for Medicare and Medicare Services (CMS) already were paying for ranibizumab for patients with neovascular AMD and the vast majority of affected patients were Medicare beneficiaries. The 2000 Clinton Initiative made it clear that routine care for patients in a clinical trial was covered by Medicare. Ranibizumab was already part of routine care and therefore it was logical to assume that it too would be covered. It was also expected that the potential cost savings to CMS from this study would serve as strong motivation for collaboration. This was acknowledged by CMS leaders early on, but the statutory authority of CMS to assist in the study was limited. The CATT leadership was told that to fully achieve the funding and masking that we requested would require “an act of Congress.” In addition, some concern was raised as to whether ranibizumab could indeed be covered in the trial by the existing Medicare Clinical Trial Policy.
Four months later (November 2006), the CATT leadership learned at an Institute of Medicine forum, where they had been asked to present these study related issues, that CMS lawyers had narrowly interpreted existing Medicare Clinical Trials Policy as forbidding the use of CMS funds for payment for ranibizumab within CATT. Despite alternative interpretations by officials in other branches of the National Institutes of Health and many Medicare carriers, the central CMS lawyers viewed the FDA-approved ranibizumab as investigational within CATT and not eligible for reimbursement. Over the next 14 months, the CATT leadership engaged in a steady stream of efforts to secure payment for ranibizumab for patients in the trial. Their efforts resulted in four important policy changes and clarifications that will be a lasting legacy of the CATT:
1) Drug Coverage: On July 9, 2007, the Revised Medicare Clinical Trial Policy was published. This policy change, driven in part by the CATT, and specifically stated that CMS could in fact pay for a drug (ranibizumab) in a clinical trial if that drug was otherwise available to Medicare beneficiaries outside of the study.
2) Masking: Over a six month period, CMS staff worked closely with the CATT to develop an AMD Demonstration Project that would have facilitated payment and masking of the study drugs. The project addressed many problems of billing for and maintaining masking of a drug when the injecting physician has no knowledge of the identity of the drug. In May, 2007 the AMD Demonstration Project was approved by CMS. However, it was not granted final approval by the Office of General Counsel (OGC). Although the Demonstration Project never became operational, it significantly stimulated discussion on these issues and contributed to the development of a National Public Forum on the Impact of Payment Policy on Clinical Trials hosted by CMS in September 2007 at which time issues raised by the CATT were presented. In addition, it is anticipated that the project may serve as a blueprint for payment of drug and patient care costs in a future NIH-sponsored trials.
3) Co-Pays: The issue of who can legally pay for a co-pay was clarified. The only entity that can legally pay a Medicare co-pay is another federal entity. As such, the NEI can pay a co-pay in the CATT and have committed funds to do so.
4) “Act of Congress”: The recent Medicare bill that rescinded the 10.6% fee cut also contained an amendment that granted to the Secretary of DHHS the authority to develop alternative payment mechanisms for items and services provided in an NIH sponsored trial if these mechanisms will enhance the scientific integrity (masking of drug) of the trial. This is the authority that the CATT needed from the very beginning. This amendment was proposed by the CATT leadership and introduced as part of a bill through the offices of Senator Herb Kohl (Democrat, Wisconsin). The bill passed on July 15, 2008.
By the end of this long process, the initial goal of providing study drug to CATT patients with no out-of-pocket expense was achieved. Lucentis is billed to CMS and 80% is covered as per the Revised Medicare Policy. Supplemental insurance policies will cover the remainder of the cost. In cases where the patient has no supplemental policy (estimated at 15% or less of patients), the NEI can legally pay the co-pay. While the Congressional amendment to the Medicare bill is too late to benefit the CATT directly, the leadership of the study was determined to prevent these delays from ever happening again and to clear the way for other comparative clinical trials that will follow.
In February, 2008, the first patients were enrolled in the CATT and by the end of July, more than 250 had enrolled. (Editor’s Note: As of October 10th, more than 400 patients are now enrolled.) Eligibility criteria for the trial are broad. Patients must have previously untreated CNV with the lesion or sequelae of the lesion (eg, blood, retinal pigment epithelium detachment, fluid) under the center of the fovea. While lesion composition (ie, classic or occult CNV) is assessed by the CATT Photograph Reading Center, there are no eligibility criteria related to lesion composition. Visual acuity must be between 20/25 and 20/320, inclusive.
Patients are assigned through randomization with equal probability to one of four groups for treatment during the first year (see below). The doses are 0.5 mg {0.05 ml} for ranibizumab and 1.25 mg {0.05 ml} for bevacizumab.
Retreatment decisions in the two variable (as needed) dosing arms of the study are driven primarily by findings on the OCT. If any subretinal, intraretinal, or sub-RPE fluid is apparent on any of the 6 slow map scans, the eye is treated. If there is no fluid on OCT, but there are other signs of active CNV, the eye is treated. These signs include new subretinal or intraretinal hemorrhage, persistent subretinal or intraretinal hemorrhage, decreased visual acuity relative to the last visit without another explanation, increased lesion size on fluorescein angiography relative to the last angiogram, or leakage on fluorescein angiography. Fluorescein angiography is required at specific visits and may be used in deciding whether treatment is warranted. Fluorescein angiography may be obtained at other visits to aid in the decision on whether treatment should be applied.
The primary outcome measure is change in visual acuity. Secondary outcome measures include number of treatments, retinal thickness at the fovea, adverse events, and cost. At the 12-month visit, patients in the fixed schedule groups will be randomly assigned continue on the fixed schedule for a second year or to receive treatment according to the guidelines for variable schedule dosing. A total of 1200 patients will be enrolled and followed through two years.
The basic questions of the relative efficacy of ranibizumab and bevacizumab remain unanswered. All retinal specialists are eager to identify ways to decrease the frequency of injection. However, there is still no convincing data on whether any of the various approaches to decreasing treatment frequency provide the same level of visual acuity benefit as monthly dosing. The CATT will provide answers to these important questions, but the timing of those answers is entirely dependent on the rate of enrollment. More than 200 retina specialists are participating through more than 40 clinical centers (see http://www.nei.nih.gov/CATT or http://clinicaltrials.gov/ct2/show/NCT00593450 for a list of participating centers). The retina community and all patients with AMD will benefit from the results of CATT. There has never been a better time to consider referring a new neovascular AMD patient to a CATT clinical center for enrollment.
Since that time I have written about Avastin vs. Lucentis 24 additional times, and about the CATT Study a previous 7 times. When I inquired earlier this month about the status of the CATT Study, Maureen Maguire was kind enough to send me a copy of the article she and Drs. Martin and Fine had submitted to Retina Times for publication in its Fall 2008 issue. I requested permission from both the editor of Retina Times and the three authors to reprint their story in my Journal to allow for wider publication than just the membership of the American Society of Retina Specialists (ASRS). I thank all involved for their cooperation in this effort.
Re-printed with permission of the authors and the American Society of Retina Specialists (ASRS). This article appears in the Fall 2008 Issue of Retina Times, the official publication of the ASRS, and is accessible by members only. For information about the ASRS, please go to www.asrs.org.
Comparison of AMD Treatments Trials (CATT): Lucentis – Avastin Trial
Daniel F. Martin MD, Maureen G. Maguire PhD, and Stuart L Fine MD
Drs. Daniel Martin (Emory University) and Stuart Fine (University of Pennsylvania) are Co-Study Chairs for the CATT Study, while Dr. Maureen Maguire (Director of the Coordinating Center at University of Pennsylvania) is the CATT Study Director.
Published in the Fall 2008 issue of Retina Times
Just over 3 years ago, two major events dramatically transformed the treatment of choroidal neovascularization (CNV) due to age-related macular degeneration (AMD). On July 17, 2005, the results of the MARINA trial comparing ranibizumab (Lucentis®) to placebo for the treatment of minimally classic and occult CNV were presented at the annual meeting of American Society of Retina Specialists meeting in Montreal. Patients assigned to ranibizumab were not only much more likely to maintain visual acuity (VA), but also had improvement in VA in unprecedented numbers. A few moments later, Philip Rosenfeld, MD, PhD presented a paper on the beneficial short-term effect of intravitreal injection of bevacizumab (Avastin®) in a single patient with neovascular AMD.
These events set off an explosion of controversy and debate on topics ranging from the penetration of molecules of different molecular weights through the retina to the ethics of off-label use of an untested agent when a well-studied, highly efficacious, and relatively safe drug was available, albeit at a very high price. By June 30, 2006 when the Food and Drug Administration approved ranibizumab for treatment of neovascular AMD, the data from additional Genentech randomized trials had provided strong evidence that ranibizumab’s efficacy and safety extended to a wide spectrum of neovascular lesions. In addition, substantial information on the pharmacokinetics, safety, and changes in vision after treatment with bevacizumab had accumulated, and the use of bevacizumab had become fully entrenched in many vitreoretinal practices.
The time was ripe for a head-to-head comparison to establish the relative efficacy and safety of these two drugs and to determine whether treating less than monthly with either drug could provide the same beneficial results on vision as the monthly injections. Led by investigators at Emory, University of Pennsylvania, and Duke, grant applications were submitted in January 2006 and received expedited peer review. In October 2006, the National Eye Institute approved funding for the Comparison of AMD Treatments Trials (CATT) – Lucentis-Avastin Trial.
Once funded, the major task that remained was to secure funding for the cost of ranibizumab and bevacizumab. The NEI grant covered the cost of purchasing, repackaging, and distributing Avastin. However, the $25 million drug cost for ranibizumab was not covered. This was anticipated and the CATT leadership had begun discussions with CMS early in the development of the trial design. The Centers for Medicare and Medicare Services (CMS) already were paying for ranibizumab for patients with neovascular AMD and the vast majority of affected patients were Medicare beneficiaries. The 2000 Clinton Initiative made it clear that routine care for patients in a clinical trial was covered by Medicare. Ranibizumab was already part of routine care and therefore it was logical to assume that it too would be covered. It was also expected that the potential cost savings to CMS from this study would serve as strong motivation for collaboration. This was acknowledged by CMS leaders early on, but the statutory authority of CMS to assist in the study was limited. The CATT leadership was told that to fully achieve the funding and masking that we requested would require “an act of Congress.” In addition, some concern was raised as to whether ranibizumab could indeed be covered in the trial by the existing Medicare Clinical Trial Policy.
Four months later (November 2006), the CATT leadership learned at an Institute of Medicine forum, where they had been asked to present these study related issues, that CMS lawyers had narrowly interpreted existing Medicare Clinical Trials Policy as forbidding the use of CMS funds for payment for ranibizumab within CATT. Despite alternative interpretations by officials in other branches of the National Institutes of Health and many Medicare carriers, the central CMS lawyers viewed the FDA-approved ranibizumab as investigational within CATT and not eligible for reimbursement. Over the next 14 months, the CATT leadership engaged in a steady stream of efforts to secure payment for ranibizumab for patients in the trial. Their efforts resulted in four important policy changes and clarifications that will be a lasting legacy of the CATT:
1) Drug Coverage: On July 9, 2007, the Revised Medicare Clinical Trial Policy was published. This policy change, driven in part by the CATT, and specifically stated that CMS could in fact pay for a drug (ranibizumab) in a clinical trial if that drug was otherwise available to Medicare beneficiaries outside of the study.
2) Masking: Over a six month period, CMS staff worked closely with the CATT to develop an AMD Demonstration Project that would have facilitated payment and masking of the study drugs. The project addressed many problems of billing for and maintaining masking of a drug when the injecting physician has no knowledge of the identity of the drug. In May, 2007 the AMD Demonstration Project was approved by CMS. However, it was not granted final approval by the Office of General Counsel (OGC). Although the Demonstration Project never became operational, it significantly stimulated discussion on these issues and contributed to the development of a National Public Forum on the Impact of Payment Policy on Clinical Trials hosted by CMS in September 2007 at which time issues raised by the CATT were presented. In addition, it is anticipated that the project may serve as a blueprint for payment of drug and patient care costs in a future NIH-sponsored trials.
3) Co-Pays: The issue of who can legally pay for a co-pay was clarified. The only entity that can legally pay a Medicare co-pay is another federal entity. As such, the NEI can pay a co-pay in the CATT and have committed funds to do so.
4) “Act of Congress”: The recent Medicare bill that rescinded the 10.6% fee cut also contained an amendment that granted to the Secretary of DHHS the authority to develop alternative payment mechanisms for items and services provided in an NIH sponsored trial if these mechanisms will enhance the scientific integrity (masking of drug) of the trial. This is the authority that the CATT needed from the very beginning. This amendment was proposed by the CATT leadership and introduced as part of a bill through the offices of Senator Herb Kohl (Democrat, Wisconsin). The bill passed on July 15, 2008.
By the end of this long process, the initial goal of providing study drug to CATT patients with no out-of-pocket expense was achieved. Lucentis is billed to CMS and 80% is covered as per the Revised Medicare Policy. Supplemental insurance policies will cover the remainder of the cost. In cases where the patient has no supplemental policy (estimated at 15% or less of patients), the NEI can legally pay the co-pay. While the Congressional amendment to the Medicare bill is too late to benefit the CATT directly, the leadership of the study was determined to prevent these delays from ever happening again and to clear the way for other comparative clinical trials that will follow.
In February, 2008, the first patients were enrolled in the CATT and by the end of July, more than 250 had enrolled. (Editor’s Note: As of October 10th, more than 400 patients are now enrolled.) Eligibility criteria for the trial are broad. Patients must have previously untreated CNV with the lesion or sequelae of the lesion (eg, blood, retinal pigment epithelium detachment, fluid) under the center of the fovea. While lesion composition (ie, classic or occult CNV) is assessed by the CATT Photograph Reading Center, there are no eligibility criteria related to lesion composition. Visual acuity must be between 20/25 and 20/320, inclusive.
Patients are assigned through randomization with equal probability to one of four groups for treatment during the first year (see below). The doses are 0.5 mg {0.05 ml} for ranibizumab and 1.25 mg {0.05 ml} for bevacizumab.
- Ranibizumab on a fixed schedule of every 4 weeks
- Bevacizumab on a fixed schedule of every 4 weeks
- Ranibizumab on variable schedule dosing; i.e., after initial treatment, monthly evaluation for treatment based on signs of lesion activity
- Bevacizumab on variable schedule dosing; i.e., after initial treatment, monthly evaluation for treatment based on signs of lesion activity
Retreatment decisions in the two variable (as needed) dosing arms of the study are driven primarily by findings on the OCT. If any subretinal, intraretinal, or sub-RPE fluid is apparent on any of the 6 slow map scans, the eye is treated. If there is no fluid on OCT, but there are other signs of active CNV, the eye is treated. These signs include new subretinal or intraretinal hemorrhage, persistent subretinal or intraretinal hemorrhage, decreased visual acuity relative to the last visit without another explanation, increased lesion size on fluorescein angiography relative to the last angiogram, or leakage on fluorescein angiography. Fluorescein angiography is required at specific visits and may be used in deciding whether treatment is warranted. Fluorescein angiography may be obtained at other visits to aid in the decision on whether treatment should be applied.
The primary outcome measure is change in visual acuity. Secondary outcome measures include number of treatments, retinal thickness at the fovea, adverse events, and cost. At the 12-month visit, patients in the fixed schedule groups will be randomly assigned continue on the fixed schedule for a second year or to receive treatment according to the guidelines for variable schedule dosing. A total of 1200 patients will be enrolled and followed through two years.
The basic questions of the relative efficacy of ranibizumab and bevacizumab remain unanswered. All retinal specialists are eager to identify ways to decrease the frequency of injection. However, there is still no convincing data on whether any of the various approaches to decreasing treatment frequency provide the same level of visual acuity benefit as monthly dosing. The CATT will provide answers to these important questions, but the timing of those answers is entirely dependent on the rate of enrollment. More than 200 retina specialists are participating through more than 40 clinical centers (see http://www.nei.nih.gov/CATT or http://clinicaltrials.gov/ct2/show/NCT00593450 for a list of participating centers). The retina community and all patients with AMD will benefit from the results of CATT. There has never been a better time to consider referring a new neovascular AMD patient to a CATT clinical center for enrollment.
posted by Irv Arons @ 1:13 AM
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