Thalassemia Standards of Care

1. Thalassemia Standards of Care Ellis J. Neufeld MD, PhD Egan Family Foundation Chair in Transitional Medicine, Harvard Medical School Associate Chief, Dana-Farber Boston Children’s Center for Cancer and Blood Disorders Chair, Medical Advisory Board, CAF ellis.Neufeld@childrens.Harvard.edu

2. Disclosures • No relevant disclosures

3. Definitions:“Standard Care” vs “Standard of Care” • Standard Care • The ordinary way your health system takes care of you • “Not research” • Insurance pays for it (but not necessarily without prior authorization, copays or various struggles). • Examples: The preparation of red cells for transfusion; BP checks during transfusion; combining transfusions with iron chelation is standard thal care • “Standard of Care” • An explicit statement that in some particular situation, you should be treated in this way (or you should not be treated in some other way). • Authoritative source • Based on evidence from the medical literature where evidence exists • Distinguished from individual expert recommendations

4. Why should we care? • Treatment changes over time. • Authoritative consensus statements that new developments have become “standard” can move the field. • Insurance should be paying for standard of care without hassles • Distinguish true expert consensus from fads, habits, and other forms of less rigorous reasons for care. • Instructive Examples • Cystic Fibrosis Foundation Guidelines for care of CF lung infections – saving lives • US Preventive Services Taskforce – less mammograms for younger women

5. Four Published Thalassemia Guidelines • Thalassaemia International Federation • 2008 on line • 2013/14 soon • Canadian Thalassemia Treaters • United Kingdom Thalassaemia Guidelines • Oakland Children’s (Is four enough?) DATES really matter – new ideas not captured in old guidelines Thalassemia.org Thalassemia.ca Thalassemia.com ukts.org

6. What Qualifies something as a standard/guideline • Who’s making the recommendations? (more on this later) • Quality of the underlying evidence • Expert opinion without firm data • Single cases that make an important point • Medical literature based on a few patients or chart-reviews (retrospective) • Prospective clinical studies to answer a question • Randomized controlled trials • “Evidence Based Clinical Practice Guidelines”

7. National Clearing House for Guidelines http://guidelines.gov RULES FOR EVIDENCE EVALUATION LIMITED LIFESPAN ALL GUIDELINES ON THE SITE FOLLOW THE RULES

8. Strength of Recommendations • “Weak” • Weak doesn’t mean “wimpy” • Lots of modern thalassemia practice would be “weak” recommendations if it were to be written down. • “Strong” • Strong doesn’t mean the evidence is perfect. • Some strong recommendations can be based on the flimsiest quality of evidence (expert opinion).

9. The GRADE system A LOT OF SPECFIC THALASSEMIA CARE RECOMMENDATIONS ARE NOT GRADE 1A AND SOME ARE 2C (and that’s ok)

10. Examples • Persons who need red cell transfusions should be vaccinated for the blood-borne infections Hepatitis A and Hepatitis B. GRADE 1A • Patients with Transfusion-Dependent Thalassemia should be monitored for iron overload by MRI annually. • Patients with Transfusion-Dependent Thalassemia should be monitored for iron overload (1B) by MRI (1B) annually (2C).

11. Guide to the literature (for pubmed.gov fans) • Expert opinion articles are now often called “How I treat” • These are very helpful and related to why patients should seek experts at least for second opinions (thalassemia is recently covered in the journal Blood) • Consensus Statements • M. Freed: “When the American Heart Association can’t decide what to do about a clinical problem they get a bunch of experts (who don’t agree) together at a hotel at O’Hare to opine, and then they write a consensus statement” • Clinical Practice Guidelines • Who wrote the guidelines? • What method did they use? • What conflicts of interest are disclosed? • American Society of Hematology guidelines for ITP EXCLUDED any authors who had been paid consultants for the companies making the hot new drugs in the field. This excluded many experts. This approach had strengths and weaknesses.

12. Guidelines, Drug Labels, and the spirit vs the letter of the law • Novartis-sponsored trials of Exjade in non-transfusion-dependent thalassemia (NTDT; thalassemia intermedia). • MRI in countries with adequate resources, ferritin world-wide • Trials led to labeling to start chelation with Ferritin>800 ng/mL and stop when ferritin<300 ng/mL • A guideline might borrow the same trial evidence and state the conclusion differently. (because ferritin 799 is not different from ferritin 801, and MRI is usually better) • In general, the companies should not be driving guidelines – but corporate trials sometimes drive the evidence.

13. Thalassemia Clinical Research Network TLC study Consensus statement • 2007 meeting at a hotel at Dulles Airport near Washington DC • Experts (mostly) agreed about what constitutes STANDARD CARE for thalassemia monitoring • Result was a consensus document relating what we could agree about, that formed the basis of monitoring in TLC study. • Example of an area not settled by the medical literature: Age at first MRI for iron assessment • At onset of chelation (to establish a baseline, but might require sedation) • At age when the patient can first do without sedation • Could heart iron be later than liver (heart iron overload is always later than liver, and cardiac T2* requires breath holding whereas liver T2* does not)? • Nothing about the 2007 meeting met criteria of Guidelines.gov which didn’t exist at the time.

14. What’s the CAF Medical Advisory Board view? • It’s better to have published standards than not. • Published standards should help patients/families with insurance issues. • Thalassemia standards should be as evidence-based as possible, especially when reviewing new technologies. • Non-expert (community) hematologists should rely primarily on published standards when they exist. • There are many individualized questions that cannot be addressed by rigid standards, and there is still plenty of room for expert opinion. • Families and their hematologists should consider options together when the path is not obvious. • New, cutting-edge therapies can never be in guidelines until “later” • CAF is planning to sponsor some “technology assessments” of cutting edge ideas, tests and treatments.

15. Thank you