1. 1 (5/5/06) NOPR National Oncologic PET Registry

2. 2 (5/5/06) PET Reimbursement Complex, slowly evolving process Dependent on FDA approval of PET drugs –Facilitated by FDAMA (1997) Reimbursable clinical indications –Determined by technology assessment panels of third-party payers –Process dominated by Centers for Medicare and Medicaid Services (CMS)

3. 3 (5/5/06) Medicare Coverage of PET CMS elected not to consider oncologic indications for PET broadly Rather evaluated the evidence on a cancer- specific and indication-specific basis Problematic because the specific evidence typically has not been very robust “Catch 22”

4. 4 (5/5/06) Medicare Reimbursement for Oncologic PET (2005) Diagnosis, staging, and restaging of: Non-small cell lung cancerLymphoma Esophageal cancerMalignant melanoma Colorectal cancer Head and neck cancer Staging, restaging, and Rx monitoring of breast cancer Detection of TG+/RAI– thyroid cancer Staging of cervical cancer (– CT/MRI outside pelvis) All other cancers/indicationsAll other cancers/indications –National registry

5. 5 (5/5/06) What is the NOPR? In 2000, the Centers for Medicare and Medicaid Services (CMS) expanded its coverage of positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) to a wide variety of indications for several common cancers - but not all cancers. In November 2004, CMS proposed expanding PET coverage to most other cancers, if providers collect relevant data in a CMS-approved clinical registry. CMS Initiative –Coverage with Evidence Development (CED)

6. 6 (5/5/06) The National Oncologic PET Registry (NOPR): CMS has determined that, as data accumulate, additional cancers may be covered for PET “Coverage with Evidence Development” provides clinically appropriate care during data collection, via a registry NOPR’s program covers those cancers neither specifically covered, nor non-covered, by CMS as of 2004 For low-prevalence cancers, there likely would never be adequate quality evidence to support a coverage decision All Medicare-eligible PET facilities can participate o Program entirely funded by user fees CMS reimbursement depends on timely data submission

7. 7 (5/5/06) NOPR: A Nationwide Collaborative Program Sponsored by Managed by Advisor Endorsed by Chair, Bruce Hillner, MD, Virginia Commonwealth University Co-chair, Barry A. Siegel, MD, Washington University R. Edward Coleman, MD, Duke University Anthony Shields, MD, PhD Wayne State University Statistician: Dawei Liu, PhD, Brown University Epidemiologist: Ilana Gareen, PhD, Brown University

8. 8 (5/5/06) NOPR Objectives Primary: To assess the effect of FDG-PET on referring physicians’ plans of intended patient management across the spectrum of the expanded cancer indications for FDG-PET Secondary: To assess the effect of FDG-PET on referring physicians’ plans of intended patient management in relation to: o Specific type of cancer o Specific indication for FDG-PET o Patient performance status o Physician’s role as provider of cancer treatment o Type of FDG-PET study (PET/CT vs. conventional PET)

9. 9 (5/5/06) Referring MD requests PET Referring MD requests PET Pre-PET Form Pre-PET Form PET done PET done PET interpreted & reported PET interpreted & reported Post-PET Form sent, including question for referring MD consent Post-PET Form sent, including question for referring MD consent Post-PET Form completed. Claim submitted Post-PET Form completed. Claim submitted Ongoing patient management Summary: NOPR Workflow Ask patient for consent Ask patient for consent

10. 10 (5/5/06) Pre-PET Form – 5 Questions 1.Reason for the PET Scan –(Diagnosis, Initial Staging, Restaging, Suspected Recurrence, Treatment Monitoring) 2.Cancer Site/Type 3.Disease Stage Summary NED, Localized, Regional, Metastatic, Unknown 4.Performance Status (ECOG classification) 5.Intended Patient Management Plan

11. 11 (5/5/06) Post-PET Form Questions customized by clinical Indication for PET (Diagnosis, staging, etc.) –3 - 6 questions per indication –Most require a Yes or No answer 2 Questions are asked on both the Pre-PET and Post- PET Forms –Intended Patient Management Plan –Planned Cancer Care Provider Referring Physician Consent

12. NOPR Status: May 8, 2006 through August 31, 2008 1,731 PET facilities nationwide participating (nearly 90% of all PET facilities)‏ 116,484 patients registered 94,076 patients - data entry completed Approximately 92% of patients and 96% of referring physicians consent to research use of data

13. NOPR Accrual (Cases Completed/Business Day)‏

14. Location of Participants (as of April 15, 2008)‏

15. Top Ten Cancers in NOPR registry Ovary / Uterine Adenexa Prostate Pancreas Kidney / Other Urinary Tract Bladder Small Cell Lung Stomach Non-small Cell Lung Myeloma Uterus, body

16. Top Ten NOPR Cancer Types & Indications Ovary / Uterine Adnexa – Recurrence Prostate – Initial Staging Ovary / Uterine Adnexa – Treatment Monitoring Ovary / Uterine Adnexa – Restaging Prostate – Recurrence Pancreas – Initial Staging Stomach – Initial Staging Prostate – Restaging Bladder – Initial Staging Pancreas – Suspected Primary

17. 17 (5/5/06) Major NOPR Cancer Types vs. Incidence (Patients Over Age 65) Cancer Type Total NOPR Scans (2007)* Incidence (CDC 2004) Scans per Incidence (2007) Prostate3,769116,6593.2% Ovary and Adnexa3,7069,62538.5% Pancreas3,56121,96216.2% Bladder2,66544,5706.0% Kidney/Other Urinary Tract2,62320,88612.6% Small Cell Lung2,39019,65712.2% Stomach2,34913,04818.0% Myeloma1,33610,19413.1% *Excluded Scans done for treatment monitoring

18. 18 (5/5/06) Results of NOPR Overall Change in Management: –Diagnosis, Staging, Restaging, Recurrence. –Data on 22,975 scans from May 8, 2006 – May 7, 2007. –J Clinical Oncology 2008 Treatment Monitoring –Data on 10,447 scans from May 8, 2006 – Dec 31, 2007. –In press in Cancer Individual Cancer Management –Staging, Restaging, Recurrence. –Data on 40,863 scans from May 8, 2006 – May 7, 2008. –In press in J Nuclear Medicine

19. 19 (5/5/06)

20. 20 (5/5/06) Cohort Profile First year of NOPR (5/8/06 to 5/7/07) 22,975 “consented” cases from 1,519 facilities Technology profile –84% PET/CT –71% non-hospital –76% fixed sites NOPR continues; > 90,000 PET studies to date Hillner et al., J Clin Oncol 2008

21. 21 (5/5/06) PET Changed Intended Management in 36.5% of Cases Non-TreatTreat23.231.628.629.228.3 TreatNon-Treat7.9 7.59.78.2 Patients with change post-PET (%) 31.139.536.139.0 36.5 Hillner et al., J Clin Oncol 2008 Clinical Indication for PET Study (Percent) Pre-Pet Plan Post-PET Plan Dx n=5,616 Staging n=6,464 Restaging n=5,607 Recurrence n=5,388 All n=22,975 TreatSame16.046.515.820.425.5 Non-TreatSame52.914.048.040.737.9

22. 22 (5/5/06) Changes in Intended Management (%) Stratified by Pre-PET Plan Image n=9,518 Biopsy n=3,552 Watch n=2,199 Treatment n=7,706 Post-PET Plan Image5.86.04.63.0 Biopsy9.524.09.06.8 Watch37.233.662.315.6 Same RxNA 42.4 New or Major Change in Rx 47.636.324.18.7 Minor change RxNA 23.5 Pre-PET Plan Hillner et al., J Clin Oncol 2008

23. 23 (5/5/06) Cancer Specific Change in Management (1 of 2) DiagnosisStagingRestaging Suspected Recurrence Bladder44.3 (174) 39.9 (1,461) 36.4 (1,239) 36.7 (878) Brain31.6 (158) -- 40.5 (222) Cervix---36.1 (341) 26.9 (353) 35.9 (290) Kidney25.4 (710) 41.1 (895) 34.4 (979) 32.4 (1,059) % (patients)

24. 24 (5/5/06) Cancer Specific Change in Management (2 of 2) DiagnosisStagingRestaging Suspected Recurrence Ovary35.3 (306) 43.2 (378) 37.7 (1,971) 44.5 (2,160) Pancreas30.2 (1,190) 39.2 (1,491) 38.3 (1,021) 39.3 (802) Prostate28.0 (321) 32.0 (2042) 34.0 (1,477) 39.4 (1,790) Small Cell Lung 21.7 (281) 43.3 (1,082) 40.8 (1,357) 38.1 (544) Myeloma--52.2 (402) 46.4 (1009) 50.9 (373)

25. 25 (5/5/06) Imaging-adjusted Change in Management Inclusion of cases where the pre-PET plan was alternative imaging (CT or MRI) may overestimate the impact of PET As a lower boundary of the impact of PET on intended management, we re-analyzed the data assuming no benefit from the information provided by PET in cases with a pre-PET imaging plan (all such cases were included in the denominator)

26. 26 (5/5/06) Cancer Specific Change in Management The overall change averaged 38.0%, ranged from 48.7% in myeloma to 31.4% in non-melanoma skin cancer. Across indications (staging, restaging, recurrence) PET only had a greater impact in myeloma. The imaging adjusted impact averaged 14.7%, ranged from 16.2% in ovarian cancer to 9.6% in non- melanoma skin cancer. Imaging adjusted change for myeloma was 11.5%.

27. 27 (5/5/06) Treatment Monitoring (1 of 2) Adjust Dose Or Duration of Therapy Switch To Another Therapy From Therapy To Supportive Care Total Change Bladder (768) 30.214.98.353.5 Brain (89) 30.314.615.760.6 Cervix (145) 32.413.18.954.4 Kidney (760) 24.115.65.245.0 % (patients)

28. 28 (5/5/06) Treatment Monitoring (2 of 2) Adjust Dose Or Duration of Therapy Switch To Another Therapy From Therapy To Supportive Care Total Change Ovary (1,995) 30.2 15.0 8.353.5 Pancreas (1,269) 28.6 15.4 4.348.4 Prostate (884) 22.5 13.9 6.743.2 Small Cell Lung (975) 28.2 17.4 7.453.1 Testis (32) -- Combined 28.1

29. 29 (5/5/06) Strengths “Real world” data Timely data Very large patient cohorts Current technology (85% PET/CT) Good observational studies usually match controlled studies in magnitude and direction of effect (Concato NEJM 2000; Benson NEJM 2000; Ionnanidis JAMA 2001) Results similar to a more tightly managed single- institution study (Hillner 2004)

30. 30 (5/5/06) Limitations Collected change in “intended” management, not actual management Unknown if management changes were in the correct direction or improve long-term outcomes NOPR does not address: –Whether PET should be used in lieu of or as a complement to other imaging techniques –The optimal sequencing of CT, MRI and PET. –How much ‘better’ is PET than next best legacy method

31. 31 (5/5/06) Summary Change in intended management associated with PET in previously non- covered cancers was similar to that reported in single-institution studies of covered cancers. ~1/3 of older patients undergoing PET for cancer types covered under Medicare’s CED policy had a major change in intended management, including type of treatment. Examination of individual cancers did not find a significant difference in treatment changes between cancer. NOPR has not yet examined if PET actually changed patient management or if PET improved outcome (can be examined in future studies). CMS is considering our application to expand the use of PET to other cancers.

32. 32 (5/5/06) MedCAC Meeting Held August 20, 2008 Technology assessment presentation NOPR results – Dr. Hillner SNM/ARC/AMI presentation – Dr. Mankoff Ovarian Cancer National Alliance International Myeloma Foundation Open comments

33. 33 (5/5/06) Comment Letter Require clear record of clinical question Provide additional guidance on usage Require accreditation or experience requirements Limit new coverage for body FDG-PET to PET/CT Continue NOPR for therapy monitoring