1. Mallinckrodt Institute of Radiology
Impact of PET on the Management of Patients with Cancer: What We Have Learned From NOPR
Barry A. Siegel, M.D.
Mallinckrodt Institute of Radiology

2. Barry A. Siegel, M.D. Disclosures
Advisory Board
GE Healthcare
Consulting
ImaginAb
Blue Earth Diagnostics
Lecture Honoraria
Siemens

3. Dissemination of PET into clinical practice has been very slow!
Barriers
Expensive technology
Slow acceptance by clinicians
Reliable supply of radiopharmaceuticals
Regulation of radiopharmaceutical production
Variable and restrictive coverage policies by government and private payers (reflecting lack of definitive evidence of utility)

4. PET Reimbursement in the USA
Dependent on FDA approval of PET drugs
Unique approach, aided by legislation
Reimbursable clinical indications
Determined by technology assessment panels of third-party payers
Process dominated by Centers for Medicare & Medicaid Services (CMS)

5. Medicare Coverage of PET
Standard for reimbursement is “reasonable and necessary”
In 1990s, CMS adopted a new evidence-based approach for making coverage determinations
Requires peer-reviewed scientific evidence to document that new technology leads to changes in patient management and to improved health outcomes for Medicare beneficiaries
Prompted in part by poor quality of evidence used to support MRI coverage

6. PET Became the “Whipping Boy” of High Technology Medicine
The MRI Backlash
PET Became the “Whipping Boy” of High Technology Medicine
PET
Payers
MRI

7. Challenges with Diagnostics
Determining “value” is a barrier for all diagnostics
Traditional blood assays, genetic profiling, or imaging
Testing is a single node in a chain of diagnostic and therapeutic interventions
Can one attribute improvements in health outcomes directly back to any single event in the chain, let alone a diagnostic imaging test?
Usefulness of a diagnostic is constrained by the (non)availability of good therapies

8. Medicare Coverage of Oncologic 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”

9. Does PET Improve Health Outcomes in Patients with Cancer?
This has been very difficult to demonstrate
Vast majority of PET clinical trials
Single-institution
Pilot  phase II
Small patient numbers (<50)
A major reason for unfavorable technology assessments of PET (and for limited coverage)

10. Does PET Improve Health Outcomes in Patients with Cancer?
Evidence accruing in the last few years
Randomized controlled trials
All done in countries with highly restricted PET coverage
Practice-based evidence (e.g., registries)
Change in management largely used as a “surrogate” for improved outcome (especially avoidance of futile therapies)

11. RCTs: FDG-PET in Oncology
Cancer (Indication)
No. RCTs
Results
NSCLC (preoperative staging) 5
Mixed, but favor reduction in futile thoracotomy
Colorectal cancer (liver metastasis resection) 2
Conflicting results with respect to reduction in futile surgery
Colorectal cancer (recurrence detection) 1
Earlier detection and increased likelihood of complete resection of recurrence
Cervical cancer (Treatment of extrapelvic disease guided by PET)
No improvement in OS or DFS
ITT Analyses: no improvements in survival. But should a diagnostic test be expected to improve survival?
No practical way to fund RCTs for each tumor/indication!

12. Evolving Role of FDG-PET for Response Assessment and Treatment Monitoring
More reliable than anatomical imaging for determining end-of-treatment response
Now standard of care in Hodgkin and aggressive non-Hodgkin lymphoma
Early monitoring during therapy allows for:
Response adaptation in high- and low-risk patients
Discontinuation of ineffective (expensive) therapy
Conflicting results to date of adaptive trials

13. Medicare Coverage of Oncologic PET
1998 Evaluation of solitary pulmonary nodules and initial staging of NSCLC
Suspected recurrent colorectal cancer, lymphoma,
2001 Further coverage for 6 prevalent cancers
Individual requests submitted for several other cancers
2004
Unwieldy Approach
Proposed mechanism for expanded coverage

14. Coverage with Evidence Development (CED)
An option for coverage of promising drugs, biologics, devices, diagnostics, and procedures that would not otherwise meet Medicare’s evidentiary standards for being “reasonable and necessary”
CED links coverage to requirement that patients participate in a registry or clinical trial
Goal of longitudinal data collection to improve understanding of the new technology
First applied to biologic therapies for colon cancer, implantable cardiac defibrillators, and oncologic PET

15. National Oncologic PET Registry: A Nationwide Collaborative Program
Advisor
Sponsored by
Managed by
Endorsed by
Chair, Bruce Hillner, MD, Virginia Commonwealth University
Co-chair, Barry A. Siegel, MD, Washington University
Co-chair, R. Edward Coleman, MD, Duke University
Co-chair, Anthony Shields, MD, PhD Wayne State University
Statisticians: Dawei Liu, PhD, Fenghai Duan, PhD, Ilana Gareen, PhD, , Lucy Hanna, MS, Brown University 15

16. Objective
Assess the effect of PET on referring physicians’ plans of intended patient management
across a wide spectrum of cancer indications for PET not currently covered by Medicare
Hypothesis
PET will lead to change of patient management as often for non-covered as reported for covered cancers

17. Goals Provide access to the service (PET)
Minimize the burden to patients, PET facilities, and referring physicians
Generate evidence of reasonable quality to help CMS decide whether to expand coverage of PET
Registry to be financially self-supporting

18. Ongoing patient management including question for referring MD consent
NOPR Workflow
PET
interpreted
& reported
Ongoing patient management
Referring MD
requests PET
PET
done
Ask patient
for consent
Pre-PET
Form
Post-PET
Form sent,
including question for referring MD consent
Post-PET Form
completed.
Claim submitted

19. Pre-PET Form: Intended Patient Management
If PET were not available, your current management strategy would be (select one)?
Observation (with close follow-up)
Additional imaging (CT, MRI) or other non-invasive diagnostic tests
Tissue biopsy (surgical, percutaneous, or endoscopic).
Treatment (if treatment is selected, then also complete the following)
Treatment Goal: (check one)  Curative  Palliative
Type(s): (check all that apply)
 Surgical  Chemotherapy (including biologic modifiers)
 Radiation  Other  Supportive care
Intended management, given PET findings, asked on post-PET form

20. Key NOPR Results (Before 2009 NCD)
Overall Impact on Patient Management
Diagnosis, Staging, Restaging, Recurrence
Data on 22,975 scans from May 8, 2006 – May 7, 2007
J Clin Oncol 2008; 26:
Impact on Patient Management by Cancer Type
Confirmed Cancers
Staging, Restaging, Recurrence
Data on 40,863 scans from May 8, 2006 – May 7, 2008
J Nucl Med 2008; 49:
Treatment Monitoring
Data on 10,447 scans from May 8, 2006 – Dec 31, 2007
Cancer 2009:115:410-18

21. 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
Hillner et al., J Clin Oncol 2008

22. PET Changed Intended Management in 36.5% of Cases
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
Treat
Same
16.0
46.5
15.8
20.4
25.5
Non-Treat
52.9
14.0
48.0
40.7
37.9
Non-Treat
Treat
23.2
31.6
28.6
29.2
28.3
7.9
7.5
9.7
8.2
Patients with change post-PET (%)
31.1
39.5
36.1
39.0
36.5
Essentially uniform across different cancer types
Hillner et al., J Clin Oncol 2008; 26:2155, Hillner et al., J Nucl Med 2008; 49:1928

23. 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
i.e., outcome might be the same if CT or MRI had been done instead 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)
14.7% vs. 38.0% overall
Hillner et al., J Nucl Med 2008; 49:1928

24. Impact of PET Used for Treatment Monitoring
Chemotherapy 82%, chemoRT 12%, RT 6%
Ovarian, pancreas, NSCLC, SCLC most frequent
Metastatic disease in 54%
PET findings led to:
Switch to another therapy in 26%
Adjust dose or duration of therapy in 17%
Switch from therapy to observation/supportive care in 6%
Management change more often if post-PET prognosis worse rather than improved/unchanged (70% vs. 40%)
Hillner et al., Cancer 2009; 115:410

25. Medicare CED and Oncologic PET
2006 National Oncologic PET Registry (NOPR) begins data collection
Initial NOPR results published and expanded coverage requested
National Coverage Determination (NCD)
Expands coverage for initial treatment strategy of most cancers and for subsequent treatment strategy of several cancers
Data collection continued for other cancers
Over 90% of US PET facilities participated
Complete data for nearly 133,000 scans

26. NOPR-2009
Data collection continued for subsequent treatment strategy of remaining cancers (with minor CRF modifications)
155,540 scans with complete data submission
Primary analysis: comparison of NOPR-2006 and NOPR cohorts (J Nucl Med 2012; 53:831-7)
Restaging, recurrence or treatment monitoring known cancers
Data on 41,145 scans (2006) and 70,358 scans (2009)
“Results strongly suggest it is unlikely that new useful information will be obtained by extending the coverage of certain cancer types and indications only under CED.”

27. Medicare CED and Oncologic PET
2013 National Coverage Determination (NCD)
Further expands coverage for subsequent treatment strategy (3-scan limit) and ends FDG-PET data collection
2010 NCD for NaF-PET; CED required
NOPR opens NaF-PET registry
2014 NOPR submits request for coverage of NaF-PET (5/15/2014)

28. Oncologic FDG-PET: Final Decision Summary
Three-scan limit clearly motivated by CMS concern that PET is widely used for surveillance, which is non-covered
Virtually no evidence that using PET (or other advanced imaging) for surveillance improves patient outcomes
Surveillance has substantial costs ($$, radiation exposure, downstream testing, patient anxiety)
We need to either get the evidence or change referring physician behavior and patient expectations

29. NOPR (NaF-PET): Results
Prostate cancer (Hillner et al., J Nucl Med 2014;55:574)
68% of all patients
1,024 Initial staging
1,997 Suspected first osseous metastasis
510 Suspected progression of osseous metastases
Treat vs. non-treat change in intended management in 44% to 52% (imaging-adjusted 12% to 16%)
Other cancers (Hillner et al., J Nucl Med 2014; 55:1054)
Similar results (lower impact with suspected first osseous metastasis than for prostate cancer)
Revised

30. Strengths of the NOPR Data
“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 more tightly managed single-institution studies (e.g., Hillner 2004) and to Australian studies with outcome validation

31. NOPR Limitations Data “quality”
Potential that physicians may have been influenced by the knowledge that future Medicare reimbursement might be influenced by their responses
No control group
A fundamental problem with observational studies
Neither historical nor contemporaneous controls adequate
Collected change in “intended” management, not actual management
Partially addressed by linking NOPR plans to claims data

32. NOPR: Intended vs. Claims-inferred Management
NOPR data ( ) linked to Medicare claims
For restaging/suspected recurrence of 6 most prevalent cancers, 30-day agreement of post-PET plan and claims-inferred action (PPV) ranged from 27.3% (prostate, surgery only) to 80.9% (kidney, watching)
For initial staging of 5 most prevalent cancers, 60-day agreement of post-PET therapy plan and claims-inferred action (PPV) ranged from 30.4% (ovary, RT) to 89.5% (SCLC, systemic therapy)
Agreement similar to that in Australian studies
Hillner et al., Med Care 2013; 51:361, Hillner et al., J Nucl Med 2013;54:2024

33. Australian Prospective Studies of Impact of PET Agreement in Post-PET Plan and Actual Care ( )

34. NOPR Limitations
Unknown if management changes were in the correct direction or improve long-term outcomes
Using management change as surrogate requires prior data on test accuracy and value of therapies
Defining the relevant long-term outcomes for a diagnostic (instead of therapeutic) procedure is controversial
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’ PET is than next best method

35. Major Problem with the NOPR Paradigm
Tradeoff between data quantity/quality and access
Consequence of the self-funded model with non-engaged participants (You get what you pay for!)
Possible solutions
Funding of participating sites/referring MDs
More detailed clinical data
Information about actual management/outcomes
Better data quality will require engaged/educated participants

36. Medicare Coverage of New Oncologic PET Radiopharmaceuticals
As of 3/7/13, national non-coverage removed for new FDA-approved oncologic PET radiopharmaceuticals
Coverage at local Medicare Administrative Contractor (MAC) discretion
C-11 choline is first example
Remains to be seen if this is really a better approach than National Coverage Analysis

37. CMS PET Registries What’s Next?

38. A National Study to Evaluate the Clinical Utility of Amyloid PET
Study Chair: Gil D. Rabinovici
Co-chairs: Maria C. Carrillo, Constantine A. Gatsonis, Bruce E. Hillner, Barry A. Siegel, Rachel A. Whitmer

39. PET Amyloid Imaging IDEAS-Study.org
FDA approved as imaging biomarkers of amyloid deposits
4/ F-florbetapir
10/ F-flutemetamol
3/ F-florbetaben
9/2013 CMS NCD for amyloid PET: will cover only under CED one study per patient with intent to :
Develop better treatments or prevention strategies for AD, or, as a strategy to identify subpopulations at risk for developing AD
Resolve clinically difficult differential diagnoses (e.g., FTD vs. AD) with goal of improving health outcomes
REVISED
IDEAS-Study.org

40. After a Two-Year Gestation: IDEAS
An open-label, longitudinal cohort study to assess the impact of amyloid PET on patient-oriented outcomes in individuals meeting Appropriate Use Criteria for amyloid PET
Primary hypothesis: In diagnostically uncertain cases, knowledge of amyloid PET status will lead to significant changes in patient management, and this will translate into improved medical outcomes
IDEAS-Study.org

41. Specific Aims
Aim 1: To assess the impact of amyloid PET on patient management at 90 days
Management plans recorded via pre- and post-PET case report forms completed by dementia expert
Aim 2: To assess the impact of amyloid PET on hospital admissions and emergency room visits at 12 months
Medicare claims of study participants compared to those of concurrent propensity-matched controls who have not had amyloid PET
IDEAS-Study.org

42. IDEAS Study Much more complicated study than NOPR
Will collect more detailed information from referring MDs, as well as images (for future analysis)
Patient-centered outcomes (Aim 2) most important to CMS
Estimated sample size
Aim 1: 11,050 subjects for 30% change in management composite endpoint
Aim 2: 18,448 subjects for 10% relative reduction in hospitalization, ER visits
Expected study cost $20M (excluding cost of scans)
Timeline to coverage: at least 5 years
IDEAS-Study.org

43. Conclusions
NOPR has successfully used one pathway to help achieve coverage for PET in cancer
But pathway quite slow and burdensome
Clinical trials of new molecular imaging tracers and methods must focus, from the outset, on obtaining evidence of improved patient outcomes
Coverage with evidence development should become a standard approach for evaluating new tracers