In October 1996, the FDA approved ProstaScint (capromab pendetide), a new diagnostic imaging agent for prostate cancer, manufactured by Cytogen Corporation, Princeton, NJ.[1-5]
ProstaScint: A New Diagnotic Tool For Metastic Prostate Cancer
ProstaScint is an immunoconju-gate containing a monoclonal antibody directed toward prostate-specific membrane antigen (PSMA). Radioactive indium-111 labeling enables detection of ProstaScint by gamma camera imaging after it has localized to sites of prostate cancer expressing PSMA.
The strength of ProstaScint as a diagnostic tool is due to its binding to PSMA. Unlike prostate-specific antigen (PSA), expression of PSMA is higher in prostatic adenocarci-noma cells than in nonmalignant tissue; higher in metastatic lesions than in primary tumors; and higher in poorly differentiated cells than in nondifferentiated cells.
In addition, PSMA is expressed by prostate cancer cells in hormone-refractory patients.
The successful targeting of PSMA has enabled ProstaScint to assist with the detection of sites of occult metastatic disease that would normally be overlooked using standard imaging techniques, providing clinicians with a diagnostic tool to assist in decision-making.
For instance, preliminary data indicate that ProstaScint results can predict response to radiation therapy in patients who have a rising PSA after radical prostatectomy.
Currently, use of ProstaScint is indicated in two settings: The first is in newly diagnosed patients with biopsy-proven prostate cancer thought to be clinically localized after standard diagnostic evaluation and who are at high risk for pelvic lymph node metastases.The second is in postprostatectomy patients with a rising PSA and a negative or equivocal standard metastatic evaluation in whom there is a high suspicion of occult metastatic disease.
FDA approval for ProstaScint was based on clinical trial data comparing ProstaScint with histopatho-logic analyses of pelvic lymph node dissection for presurgical patients. For patients with recurrent disease, ProstaScint was compared with histopathologic analyses of the prostatic fossa (see Table).
Additional studies have continued to report sensitivity and specificity rates for ProstaScint that are superior to traditional tests such as MRI and CT scans.[3-5]
ProstaScint is a nuclear medicine procedure that requires extensive tomo-graphic imaging and analysis of the pelvis and lower abdomen. As a result, there is a strong learning curve effect associated with interpretation of ProstaScint scans.
Cytogen Corporation has attempted to minimize the learning curve effect by developing the scientific PIE (Partners in Excellence) program in conjunction with the American College of Nuclear Physicians (ACNP).
The PIE program is an intensive training, certification and accreditation program designed to efficiently implement ProstaScint screening throughout the United States while maintaining the highest quality for image interpretation.
While the development of the PIE program commenced prior to FDA approval for ProstaScint, the FDA agreed that formal training was an important factor in assuring accurate image interpretation. As a result, the FDA included in its official labeling of ProstaScint a requirement for formal training of all physicians who interpret ProstaScint scans, a requirement unique to the field of diagnostic testing.
The PIE program began in 1996 with the identification of sites that possessed the requisite gamma camera equipment and computer hardware to permit patients to be appropriately imaged with ProstaScint. With the assistance of Bard Urological Division, a corporate partner, sites were further prioritized according to a particular locations number of urologists and prostate cancer patients.
The PIE program consists of several steps. First, following site agreement to participate in the PIE program, a Cytogen nuclear oncology specialist meets with physicians and technologists on-site to review program requirements and provide hands-on training in image acquisition and processing. The nuclear oncol-ogy specialist is on-site for the first three to five imaging sessions.
After completion of a ProstaScint scan, images are sent to a central over-reading facility staffed by expert ProstaScint readers from the ACNP. The readers review technical aspects of the ProstaScint image and interpret significant findings, which are then forwarded to the originating PIE site before a final report on the patient is completed.
Site certification and accreditation takes place after the site satisfactorily completes 10 or more Pros-taScint scans and passes an ACNP on-site inspection. Once certified and accredited by the ACNP, the PIE site is no longer required to obtain over-reading for each ProstaScint image. How-ever, Cytogen continues to monitor image quality and offer technical assistance 24 hours a day.
The PIE programs success in addressing the learning curve associated with ProstaScint use has been evaluated in terms of improved accuracy, sensitivity, and specificity. On average, interpretation accuracy for the first and second scans conducted is 65%, increasing to 86% for the ninth and tenth scans.
Sensitivity and specificity have also shown a strong learning curve effect, with detection of pelvic lymph node metastases being significantly higher at sites performing 10 or more scans (65% sensitivity and 78% specificity) versus sites performing less than 10 (58% and 62%, respectively).[6,7]
When Pros-taScint was first launched in February 1997, Cytogens goal for the program was to have 140 operational sites after one year. This goal was surpassed in half the expected time, with 151 sites in operation at the end of August of this year.
The program continues to locate and accredit sites at a rapid pace, presenting Cytogen with the challenge of maintaining the quality and informational content of ProstaScint images in the face of increased volume. If the program continues to exceed expectations, Cytogen may have to reevaluate its protocols to ensure that increased volume does not come at the expense of quality.
Cytogens experience with the PIE program provides an important model for companies that are in the process of developing and marketing highly advanced diagnostic and treatment technologies. Several aspects of the program are especially important.
First, medicine is becoming more technically sophisticated, and learning curve effects are increasingly apparent for diagnostic tests and therapeutic procedures.[8-10] The PIE program is one of the first to formally acknowledge the clinical implications of the learning curve effect, and implementation of the program has succeeded in improving the sensitivity, specificity, and accuracy of ProstaScint scans.[6,7]
Second, organizational considerations are important in developing such a program. Cytogen took a novel approach by partnering with other organizations rather than shouldering the entire burden itself. Overall success of the PIE program requires cooperation among four separate parties: (1) Cytogens team of nuclear oncology specialists, (2) Bard Urological Divisions sales team (Cyto-gens co-marketing associate), (3) ACNP personnel, and (4) nuclear medicine physicians and technologists at the site.
Finally, the PIE program is an example of how FDA policies regulating quality assurance can be adequately addressed by companies marketing advanced medical technology.