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

Challenges in Preventing and Managing Rare Conditions in a

Publicly Funded Healthcare System

Durhane Wong-Rieger, PhDCanadian Organization for Rare Disorders

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

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


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


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


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

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

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

Down Syndrome by Country/Registry

Country/Registry DS live births, stilbirths

DS live births, stillbirths, TOP

CANADA 14.4 N/A

Alberta, Canada 11.5 16.5

Atlanta, USA 12.0 N/A

Central East France 4.9 16.2

England and Wales 6.5 11.9

Finland 10.0 21.2

Hungary 8.1 9.3

Norway 13.7 16.0

South America 17.5 N/A

United Arab Emirates 18.0 N/A

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)

Anencephaly and Spina Bifida RatesCountry Anencephaly

Live births, stillbirths

Anencephaly Live, still-

births, TOP

Spina BIfida Live births, stillbirths

Spina BIfida Live, still-

births, TOP

CANADA 0.9 N/A 4.0 N/A

Alberta, CA 1.0 1.3 3.4 3.9

Atlanta, USA 1.5 N/A 0.6 N/A

CE France 0.0 1.5 0.7 3.5

England 0.4 2.7 1.0 2.8

Finland 0.2 3.1 2.2 3.4

Hungary 0.1 2.1 1.6 3.1

Norway 2.5 5.3 4.2 6.2

So America 7.6 N/A 11.7 N/A

United Arab 7.7 N/A 6.4 N/A

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

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

Nfld & Lab 3 → 5 Adding MCAD and expanding HCY to entire province

NS, NB, PEI 11 → 15 Added 3 April, 2006 (LCHAD, MSUD

QB & Nunavut E

27 MS/MS under consideration

Ontario 3 → 28 MCAD added April 06; expanding to 28 by end 2006

MB, NWT E, Nunavut W

6 MS/MS under consideration for 2006; Manitoba offers 3 conditions to select populations

SK 34 → 36 Blood spot collection mandated by Hospitals Act adding BIO and CAH in 2006; offer another 13 to select populations or on request

AB 5 Purchased MS/MS 2005; Pilot universal hearing screening; CF universal pilot in Calgary region

BC, Yukon, NWT W

5 Purchased MS/MS 2003; expansion under review

NBS Current and Pending in Canada

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

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

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

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

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

160 New Orphan Drug Developments in Past Decade

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

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

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

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

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

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