Integrating Emerging Technologies and Evidence on the Frontline: The Oncologists’ View

1. Integrating Emerging Technologies and Evidence on the Frontline:The Oncologists’ View Amy P. Abernethy, MD Duke University Medical Center Durham, North Carolina September 14, 2009

2. Background • Hematologist & Medical Oncologist • In academic oncology practice since 2001 • Leukemia & lymphoma inpatient practice • Melanoma outpatient practice • Solid tumor palliative and supportive care • Research • Health IT and Clinical Informatics • Clinical trials • Systematic review • Policy • Disclosures

3. It’s Monday • Monday, Aug 31 • Half day multi-disciplinary melanoma clinic • 14 patients including 4 new patients • “Experimental therapies” (aka Emerging Technologies) a part of 8/14 discussions • 5 cases presented here • FDA registered • Standard of care but “experimental” • Clinical trial • Who knows? • Communication challenges !

4. It’s Monday • AA • 37 yo • Nurse, red-haired, Irish • Stage IIIB melanoma with 47% risk of death at 5 years • Standard regimen: 1 month high-dose interferon (FDA-approved), 11 months moderate dose; lowers relative risk of death ~15% and absolute risk by ~10% • Associated symptoms: fatigue, mood disturbance, autoimmune dysfunction • Greek study shows 1 month high-dose = standard regimen • Worth the loss of QOL over 11 months? • Different advice at Duke, UNC, Wake Forest, Pitt and Dr. Morse • Impact on fertility? • Clinical trial when we know the success rate with adjuvant interferon? ! ! !

5. It’s Monday • BB • 26 yo • Daughter • Administrative coordinator • Originally with a scalp melanoma, now with lung metastases • IL-2 • Temozolomide/DTIC (IV or oral) • Imatinib • Referral to NCI for a Phase II clinical trial • Fertility program referral (?ovarian tissue) ! ! ! !

6. It’s Monday • CC • 88 yo • Mother, grandmother, wife of WWII Veteran (64 yrs) • Confused  widely metastatic melanoma including brain, liver, lungs, hilar nodes • Whole brain radiation • Referred to Duke by son (Pharm D) • Clinical trial? • Mistletoe? • Rebukes suggestion of hospice • Questions if I should start mom on G-CSF ! ! !

7. It’s Monday • DD • 24 yo • Daughter, sister, surfer, recent college graduate • 22yo sister died in December of cystic fibrosis • Originally with a L shoulder melanoma • Skin/subcutaneous metastases  UNC for clinical trial • Recurrence  IL-2 • Cord compression  radiation • Preparing to go to NCI when developed brain metastases  radiation; ?stereotactic • Referral to hospice  “too early” • Referral to a Phase I trial? ! !

8. It’s Monday • EE • 60 yo • Wife & caregiver of elderly mother • Originally with a R leg melanoma and groin adenopathy, now with liver metastases • Originally delayed interferon due to need to care for her mother • Too old for IL2 • Clinical trial is first line therapy? • Funding? Eligibility? • When will it be open (compliance requirements)? • Radiofrequency ablation of liver metastases as a bridge to the study being open? ! !

9. Who Gets Access to What? • Not just about clinical trials • Experimental therapies in studies, practice, and procedures • Role of age and demographic factors? • Role of finances? • Role of data (basic, translational, clinical science, synthesized)? • Role of my knowledge, interest and perseverance? • Role of the patient and/or family’s knowledge, interest and perseverance? • What types of experimental pursuits are appropriate (survival benefit? QOL concerns like fertility?)? • What are the palliative and hospice care options?

10. It’s Monday • Human frontline • Who takes care of me? • I cry • I worry • I get angry • I need to make a living • Am I equipped with the right communication skills? • Am I equipped to deal with the repetitive trauma?

11. It’s Monday • Repetitive decision-making about experimental therapies • Toolbox • Quality • Opportunity in the setting of the urgency • Experimental therapies are a part of my language of hope • Current versions of palliative and hospice care not helpful • Timing and access • Either / or phenomenon • Rosy colored glasses of dying

12. Clinician concerns • Balancing the decision and level of evidence to support each decision within the context of magnitude of risk • Everyone wants the latest and greatest – when is it worth the risk? • Do patients and their families understand the risk? • Offer experimental treatment only in the context of clinical trials? • Access to synthesized evidence? • Need to generate evidence base • Need for safety and toxicity studies • Need for quality oversight • Individual tailoring and applicability • Assisting the activated patient • Risk of withholding treatment and inequity in distribution of resources • Potential for subtle coercion and not truly informed choice

13. Compendia do not provide reliable and unbiased evidence for off-label uses of anticancer drugs and biological agents • CMS coverage of off-label indications for anticancer drugs is limited to those listed in pre-specified compendia. • Objective: To describe the quality, timeliness, and scope of these compendia. • Methods: • Evaluated American Hospital Formulary Service-Drug Information (AHFS-DI), Clinical Pharmacology, DRUGDEX, Facts & Comparisons, and NCCN Drugs and Biologics compendia on their methodological processes for adding anticancer drugs. • Compared the evidence cited for 14 off-label indications to de novo systematic reviews of the literature in 2006, with a longitudinal review of change in off-label listings and uptake of new evidence for one off-label indication between 2006 to 2008.

14. Compendia do not provide reliable and unbiased evidence for off-label uses of anticancer drugs and biological agents • Little agreement was found between stated methodologies and actual compendia practices. • The compendia explicitly cited only a small proportion of the available evidence, which often was neither the most recent nor of the highest methodological quality. • The compendia differed among themselves in which evidence they cited as well as their terminology, level of detail, presentation and referencing of evidence. • The compendia differed in which off-label indications they included and whether and how they recommended a particular drug for a particular cancer. • Updates were not conducted in a timely manner • in-depth review of gemcitabine for bladder cancer • number of citations referenced by the compendia did not substantially increase between 2006 and 2008, despite accumulation of published evidence over that period

15. Report on the evidence regarding off-label indications for targeted therapies used in cancer treatment • Large number of phase II trials for off-label indications; • Rapid publication cycle, with short time from submission to appearance in print; • June effect • Very few (to-date) Phase III studies; • Minimal reporting standards; • Efficacy and safety difficult to determine.  ? An online, accessible, and comprehensive database/registry of case reports, with instruction to authors re: reporting of adverse events and/or efficacy, easily searchable, and with minimal barriers to submitting reports.

16. What is the perception of different stakeholders (including patients and physicians) about the state of the evidence of emerging technologies and the balance of potential benefits and harms? • What messages are reaching patients and other stakeholders from the media, direct-to-consumer advertising, or other sources? • How do we communicate what is known and what is not yet known about emerging technologies? • What role could AHRQ have in communicating the broader questions of development of emerging technologies and the need for evidence generation?

17. Integrated clinical/research environment • Availability of clinical trials and mechanisms to access experimental therapies • Pipeline stoking (investment in pre-clinic studies, rapid advancement of drugs from pre-clinical to phase I, publication of early-phase results) • Education of providers • Education of patients • Integrated clinical/research data and IT systems • Upskilling of clinical environments (especially in community-based and smaller practices)