Challenges in Preventing and Managing Rare Conditions in a Publicly Funded Healthcare System

1. Challenges in Preventing and Managing Rare Conditions in a Publicly Funded Healthcare System Durhane Wong-Rieger, PhD Canadian Organization for Rare Disorders

2. What is a Rare Disorder or Orphan Disease? • Defined by prevalence in population • Australia: affects fewer than 2,000 persons (1:9,090) • USA: affects fewer than 200,000 persons (1:1,333) • Japan: affects fewer than 50,000 persons (1:2,000) • Europe: affects fewer than 185,000 (1:2,000) • Canada: no official standard • Affects 6% to 8% of population (Eurordis) or up to 10% (USA) or 3 million Canadians • Characteristics of rare diseases • Number: 5,000 to 6,000 (NIH); 5,000 to 8,000 (Eurordis) • About 80% are genetic (chromosone or single-gene mutation) • Others due to infections, allergies, environmental factors

3. How Canadians with Rare Disorders Experience Canadian Healthcare • Misdiagnosis of Patient with CADASIL • 50-year old male patient identified and treated for 5 years as suffering from MS • Anomalies in symptoms dismissed by specialists • Lack of attention to family history typical of Cadasil • Patient suffered stroke at Christmas with loss of speech and mobility atypical of MS but typical for Cadasil • MS Clinic refused genetic testing for Cadasil “because it is a very rare condition and therefore unlikely” • Patient family finally got genetic testing on own, through local neurologist; confirmed Cadasil • Taken off MS treatment; offered genetic counseling • Diagnosed too late for clinical trial

4. How Canadians with Rare Disorders Experience Canadian Healthcare • Mother of 5-year old with rare Plasminogen deficiency • If not treated, fibrin deposits accumulate in the brain; pus-like excretions from the eyes and evenutally could lead to blindness • In the USA, standard treatment is plasminogen drops manufactured from plasma, usually done in hospital • Technology is available and easy • CBS will not produce because it is not one of their products • No Canadian hospital will manufacture because lack “sterile” laboratory conditions • Hospitals suggest that pharmaceutical companies manufacturing plasma products could produce, but companies refuse because too expensive for such a small market • Son seeing specialist in November 2006 to determine prognosis

5. How Canadians with Rare Disorders Experience Canadian Healthcare • Lack of Access to Treatment for Fabry’s Disease • Very rare genetic condition that affect 300 families in Canada • Lack of enzyme leading to accumulation of waste materials causing severe pain, liver and heart damage and early death • Enzyme replacement therapy (recombinant technology) approved by Health Canada in January 2004 but rejected by Common Drug Review as “not cost-effective” ($250,000 per patient per year) • Available in more than 40 countries worldwide • After much advocacy, agreement by F/P/T Health Ministers to fund under research protocol in 2005 • Agreement finally signed in October 2006; no new patients have been enrolled • Research protocol is both costly and redundant, leading to further delays with no new knowledge

6. How Canadians with Rare Disorders Experience Canadian Healthcare • Thalassemia patients in Toronto denied access to adult program • Thalassemia is a life-threatening blood disorder treated with regular blood transfusions and iron chelation • Treatment regimen is onerous and side effects require careful monitoring • Adult program at TGH was capped at 99 patients at a time when most patients probably did not survive to adulthood • For past 6 years, no new admissions to program with 30+ patients stuck at HSK • Physician staff at TGH reduced from 2 FT to 0.2 FT • 12 thalassemia patient deaths in past four years, many of preventable causes

7. Why is Pre-Natal Screening Needed? • 2% - 3% of newborns in Canada born with severe congenital anomalies • 7,000 – 10,000 affected newborns annually • Causes • 15%-25% = known genetic causes) • 8%-12% = environmental (maternal drug or chemical exposure) • 20%-25% = multi-factorial inheritance (age, diabetes, etc.) • 40%-60% = unexplained causes • With screening, mortality decrease from 3.1 per 1,000 (1981) to 1.9 per 1,000 (1995) = 4,200 saved lives annually

8. Impact of Prenatal Screening on Downs Syndrome in Canada • 3 key tests: Amniocentesis, CVS and Cordocentesis • Focus on Downs Syndrome, neural tube defects, congenital heart defects, oral facial cleft, limb reductions • Based on risk factors (maternal age, history, etc.) • Impact on incidence of Down’s Syndrome births • DS Constant over 10 years at 14.4/1,000 • Has remained steady, probably because of opposing factors of increasing maternal age and prenatal screening • Impact of prenatal screening => terminated pregnancies and reduced Downs Syndrome births • Canada still higher than most European countries but lower than South America and United Arab Emirates

9. Down Syndrome by Country/Registry

10. Impact of Prenatal Screening on Neural Tube Defects • Neural tube defects significantly reduced • Incidence of spina bifida reduced from 11.1 per 10,000 to 5.6 per 10,000 births annually • Due to vitamin supplementation and prenatal screening • However, Canada still higher than European countries but lower than South America (where abortion illegal)

11. Anencephaly and Spina Bifida Rates

12. What is Status of Newborn Screening? • USA and Canada are the only developed countries without a national screening program • Lack of coordinated network of newborn screening services in some areas may reduce overall effectiveness of newborn screening • Expanding newborn screening to include additional diseases (HC, GA, MSUD) beyond PKU & CH, and/or to take second specimen would save more newborns from death and disability but incremental costs per case found would be high • NBS varies in states from 4 to 60, with most at 30+ • Europe: countries vary widely in # required tests

13. Current and Pending NBS in Canada • Core Tests: PKU (phenylketonuria) and CH (congenital hypothyroidism) • Highest number: Saskatchewan with 34 • Second: Quebec with 27 • Ontario: scheduled to go from 3 to 28 in 2007 (including SCD) • Worst: Newfoundland, British Columbia, Alberta • Alberta: first province introducing CF screening

14. NBS Current and Pending in Canada

15. Genetic testing and counselling • No established protocol for notification and follow-up upon diagnosis of genetic disorder • Most families with genetic disorder have no access to genetic counselor • Canada has 1 fully accredited program (McGill) and 2 “new program” status (UBC and U of Toronto) • USA has 19 fully accredited genetic counseling programs and 7 with recognized “new program” status • Australia has five genetic counseling programs • UK has two genetic counseling programs

16. Multidisciplinary comprehensive care for are diseases: case examples • Some comprehensive care programs for specific rare disorders • Hemophilia: consensus-based Standards of Care produced with support from Canadian Hemophilia Society; multidisciplinary children and adult clinics in Ontario and Quebec and to some degree in all provinces; research program funded by CHS • Cystic Fibrosis: established clinics in all major cities, with multidisciplinary teams, and supplemental grant funding from Canadian Cystic Fibrosis Foundation and active research program • ALS/Neuromuscular clinics in all major cities with identified multidisciplinary teams • Metabolic Disorders Clinics in most children’s hospitals but lacking elsewhere

17. Lack Comprehensive Care for Most Rare Disorders • Significant under-funding, especially adult clinics, e.g., cystic fibrosis, neuromuscular, hemaglobinopathies • Example: Thalassemia Clinic at Toronto General Hospital capped for many years at 99 patients • Result: 30+ “adult” patient “backed up” at HSK • Past 4 years, deaths of 12+ young adults with thalassemia half due to “preventable” causes • Hematogists: Decline from 2 FT to 0.2 FTE (+ new PT) • Problem: lack of dedicated funding and unwillingness to allocate from general budget; no extra billing for doctors • Lack of transition programs to effect transfer to adult care and to self-management

18. Prior to 1983, Almost No Therapies for Rare Disorders • 1983 USA Orphan Drug Act • Grants, tax credits, priority review, market exclusivity • 1993 Japan Amendments • Limited grants and tax credits, priority review, market incentives • 1999 Australia Additions to Therapeutic Goods • Priority review, accept USA orphan status • 2000 European Union Regulation • Country specific grants, 10-year market exclusivity • 1996 Health Canada decides Orphan Drug Policy unnecessary

19. Canada is Only Developed Country w/o Orphan Drug Policy • 1997 Recommendation • Unnecessary because Canadians already have adequate access to orphan drugs • Orphan drugs already qualify for tax incentives; number with rare diseases may not warrant R&D in Canada • Pathways under current regulations • Fee reductions and tax credits, esp. if estimated revenues < 10x evaluation fee (not an incentive cf. international) • Access to unapproved drugs through SAP for serious and life-threatening conditions (but HC does not assure safety, efficacy or quality) • Priority reviews for serious or life-threatening • Notice of Compliance with Conditions

20. 160 New Orphan Drug Developments in Past Decade

21. Most Developed Countries: Policies for Rare Disorders and Orphan Drugs • European countries with specific public policies on rare diseases: Denmark, France, Italy, Spain and the UK • EU level • Regulation on Orphan Medicinal Products • Centres of Reference for conditions requiring concentration of expertise • Best practices developed among networks of health professionals and laboratories • In UK, when drug recommended, mandated for regional health trusts to provide • UK National Institute for Clinical Excellence Citizens Council concluded that treatments for rare disorders should not be denied because of cost

22. European Support for Rare Diseases EU Action Programme on Rare Diseases for 1999-2000 funded projects with aim to: • Ensuring a high level of health protection for EU citizens in relation to rare diseases • Improving knowledge and facilitating access to information on these diseases Priority under European Union Public Health Programme 2003-2008 with projects funded to: • Improving information and knowledge for the development of public health • Enhancing the capability of responding rapidly and in a co-ordinated fashion to health threats

23. Lack of Canadian Orphan Drug Policy • Lack of strategy to increase public awareness about and support for rare disorders • Lack of Public Health programs aimed at prevention, early detection, and diagnosis • Lack of specific professional training and expertise, including funding for centers of excellence • Lack of support for patients, families, and patient support communities (no resources) • Lack of treatment, acute and chronic disease management

24. Canadians w/Rare Disorders Among Last in World to Get New Therapies • In Canada, drugs for rare disorders cannot meet the very stringent “cost-effectiveness” applied by Common Drug Review and provincial drug plans • Drugs for rare disorders (DRD) can be significantly more expensive because of high innovative development costs with estimated return from very small number of patients • DRD may not have same level of clinical evidence because sample size is small, breakthrough therapies do not have long-term outcome data, and few new patients for follow-up trials • Public drug plans apply same criteria as to common drugs • National Pharmaceutical Strategy has identified “Expensive Drugs for Rare Disorder” as priority but no action plan