La Doctora Virginia Llera, Virginia A. Llera ofreció una conferencia el 17/09/2014 en la Fundación Ramón Areces. Llera es la Fundadora de la primera organización de Enfermedades Raras y drogas huérfanas en Latino América y Caribe, GEISER, y Presidenta del Foro Internacional, ICORD (International Conference on Rare Diseases & Orphan Drugs). Su conferencia, titulada 'Optimizando los procesos de investigación en enfermedades raras y medicamentos huérfanos', tuvo lugar dentro del ciclo sobre patologías poco frecuentes organizado por Fundación Ramón Areces en colaboración con Vall d'Hebron Institute of Research, Barcelona.

1. Marlene E. Haffner, MD, MPH
CEO, Haffner Associates, LLC
Center for Drug Research and Development
U of British Columbia
Vancouver, Canada
Tuesday, October 16, 2012

3. 
◦ Patent expiration
◦ Generic Competition
◦ Dryyingg Pippelines
◦ Biosimilars
◦ Regulatory Guidelines
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◦ Reduction in ROI
◦ Lack of Success
◦ EEconomiic UUncertaiinty
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4. • Limited public awareness ሺinvisible patient populationሻ
• Scarcity off cllinicall expertise andd refference centers – ddisease is
poorly understood; no natural history
• Delay in diagnosis
• Small patient population – difficulty in recruiting to clinical
trials
•• GGeeooggrraapphhiicc ddiissppeerrssiioonn
• Life threatening/chronic
• Heterogeneous conditions
• Difficult to stratify/stage – lack of natural history of disease
• Limited treatment availability

6. Orphan Disease Per 100, 000 People
Guillain-Barre syndrome 50
Melanoma, familial 50
Autism, genetic types 45
Scleroderma 40
Focal dystonia 30
Marfan syndrome 30
Non-Hodgkin malignant lymphoma 30
Retinitis pigmentosa 28
Gelineau disease (Narcolepsy) 26
Myeloma, multiple 25
Alpha-1 antitrypsin deficiency 25
Diaphragmatic hernia, congenital 25
Source: Orpha.net

7. 
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R&D Drivers Commercial Drivers
Tax Credits Favorable reimbursement
R&D Grants Fewer hurdles to approval
Filing fees reduced or waived Longer/stronger exclusivity
Shorter development timelines Lower marketing costs
Greater Regulatory Success Faster Uptake
Global Support Premium Pricing
Source: Thomson Reuters Newport
Premium, IMS Health

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9. Designation

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◦ cchhaaiirr, 11 ffrroomm eeaacchh MMSS, 33 ppaattiieenntt oorrggaanniizzaattiioonn mmeemmbbeerrss, 33
from CHMP, 1 each Norway, Lichtenstein, Iceland, 1 from EC
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◦ PPhharmaceuticall AAffffairs LLaw AAmenddment ሺሺ11999933ሻሻ
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13. Nation Programs Challenges
India Indian Drugs Manufactures Associationሺ2001ሻ
requested the government to institute the Orphan
Drug Act
Enforcing Patent Laws and Market
exclusivity
Act.
Taiwan Rare Disease and Orphan Drug Act ሺ2009ሻ
159 classified rare diseases
77 approved orphan products
Regulation Efficiency
Safety Measures
Local drug development
South Korea Designation ൌ Prevalence ൏ 20,000 and diseases with
no treatment in Korea
130 Orphan products approved
Regulation through KFDA
Usage limitations
Hong Kong New Chemical Entity Registration Process Process Time
Singapore Singapore’s Medicine Act ‐Inactive Definition is unclear; there is
mentioning yet no details
South Africa South African Foundation ffoorr RRaarree DDiissoorrddeerrss NNoo ssttrreennggtthh, ccoommpplliiaannccee, ffuunnddiinngg
Australia Designation ൌ Prevalence ൏ 2,000
Focused on particular populations
Not defined in law
Source: Sharma, Abraham, Manas, & Dushyant. "Orphan
Drug: Development Trends and Strategies."

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15.  1 in 12 Canadians has a rare disease (CORD)
 Most of the rare diseases go undiagnosed and untreated
 No reference in Food and Drugs Act and Regulation
 More than ½ of orphan drug products approved in US
& Europe are not available in Canada ($$$)
 FDA-approved drug license in Canada
 Canadians pay an estimated $82 million/year on orphan
drug†
 Concerns re price and QALY

16.  Alberta
◦ First to develop Rare Diseases Drug Program on April 1, 2009
◦ Defines orphan as less than 1 in 50,000
◦ Program only covers drugs for five rare diseases
 Ontario
◦ Defines orphan as 1 per 100,000-150,000
◦ Framework developed January 2010
◦ Ministry created an expert review process to help align
potential patients with available OD therapies
 Heavily dependent on Provincial Public Drug Plans
◦ Budget constraints
◦ Other provinces?

17.  Allows the distribution of drugs that are unavailable for
sale to medical personnel (Emergency)
 Provides access to treatments for rare disorders
 Provides legal accesses – no safety assurance
 Requires reporting of all outcomes
 Drugs Directive Renewal Process
◦ Special Access Program (1996)
◦ Preauthorization Waived
◦ Physician Awareness

18.  Priority Review
◦ First entry new active substance
◦ Serious, life-threatening or severely debilitating disease or
condition
◦ Important therapeutic Gain
 Conditional Approval
◦ Post –marketing confirmatory studies
◦ Non-renewal

19.  Investigational New Drugs
◦ Review process that oversees the safety of proposed clinical research
◦ Provides assistance to manufacturers in clinical trial designation and
development
 Drug Evaluation Fees Regulation
◦ Provision for the reduction of fees for drugs in smaller markets
 Patent Protection, The Patent Act
◦ 20 years from file data
◦ No patent term extension
 Research & Development Incentives, The Income Tax Act
◦ Provides tax credit to R&D for the advancement of science

20.  Finding of Rare Disease Genes in Canada
 Funded by Advancing Technology Innovation through
Discovery
 Consortium of doctors and scientist
 Lead by University of Ottawa, University of British
Columbia, Research Center CHU Sainte-Justine
 Goals
◦ Identification of patients
◦ Identification of disease-causing genetic changes
◦ National Data Coordination Centre  improve sequencing
◦ Ethical guidelines for sequencing

21.  Partnership between Medunik Canada and Orphan Europe
distribution agreement
 Medunik Rights to Market
 Therapies
◦ Acute Hepatic Porphyria
◦ Patent Ductus Arteriosus
◦ Hyperammonaema due To N- acetylglutamate Synthase (NAGS) or 1
of 3 organic acidurias
◦ Vitamin E deficiency in Chronic Cholestasis
 QOLMedical (2011)
◦ Sucraid (sacrosidase)
◦ Ethamolin (Ethanolamine Oleate)

22.  National network for organizations that represent rare
diseases
 Provides information on/to support groups
 Involved in legislative measures
◦ Development of Orphan Drug Policy
◦ Expensive Drugs for Rare Diseases Program
 New-born Screening Initiative
 Director – Durhane Wong-Rieger, PhD

23.  Past approach on Orphan Drug Regulation
 New modern framework (Oct. 3, 2012)
◦ Development, Evaluation, and Approval
 Orphan Definition / Criteria
 Key focus
◦ International collaboration (information-sharing)
◦ Resource Efficiency for Canadian Scientist
◦ Improved safety and effectiveness monitoring
 Benefits – so far – no exclusivity or tax incentives
 Timeline - will go for public consultation

24.  Reference portal for individuals with rare diseases
 Becomes a national team of Orphanet Consortium
 In-kind support through Institute of Genetics (CIHR)
 Responsibilities
◦ collection of information on
 specialized clinics / expert centers
 medical laboratories
 ongoing research / clinical trials
 patient organizations
 Registries/ biobanks
◦ Create a national entry site to Orphanet

25. Relative contribution of Top-15 countries to the total
scientific output for the 88 rare metabolic disorders††
1996‐1998 2009‐2011
OUT
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† De Vrueh, Remco. "China Has Joined the Fight
against Rare Disorders."

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◦ Product must be safe and effective for its intended use
◦ NNoott aallwwaayyss eeaassyy ttoo ddeemmoonnssttrraattee
◦ Frequent post‐marketing commitments
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◦ 80% genetic
◦ 90 % Serious and/or life threatening ሺሺUSሻሻ; 100%
serious/life threatening ሺEUሻ
◦ 50% children

29. 
◦ EEUU hhaass wwhhiittee ppaappeerr
◦ FDA will have guidance
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◦ FFoouunnddeerr eeffffeecctt
◦ Cultural norms

30.  Protocol assistance/pre‐IND meetings – used in US and
EU and Japan. No charge
 FDA – Office of Orphan Products Reviews designation
aanndd RReevviieeww DDiivviissiioonn ggrraannttss pprroodduucctt aapppprroovvaall. CCoonnssuulltt
with each other. Office of Rare Diseases in CDER – works
with orphan product policy in CDER
 EU – COMP reviews designation with concurrence by EC.
Approval by CHMP with concurrence by EC
 CCoonnccoorrddaannccee bbeettwweeeenn EEUU aanndd UUSS pprroobbaabbllyy ൐൐9900%%
◦ Differences with disease definition
◦ And population numbers

31.  PDUFA 5/FDASIA – Section IX
◦ TTo impllement more effffective processes ffor expedditedd
development and review of innovative new drugs to meet unmet
needs § 901 ሺaሻ
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◦ Helpful for Orphan Products
◦ Helpful for new FDA reviewers
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33.  Big PhRMA increasing involvement in Orphan Product
Developpment
 Asian Markets ‐ emerging
 Gene therapy – on the horizon
 IImmpprroovveemmeennttss iinn DDiiaaggnnoossiiss//TTrreeaattmmeenntt//ggeenneettiicc mmaarrkkeerrss
 Need for more Natural History Data
 Issues of Access/Cost ‐ especially in individual Member
SSttaatteess
 New platforms
 Chronic therapy – long lived products
 CCanadda hhas some prodducts avaiillabblle, bbut….
 Over all ‐ exciting, new technology, serving unmet needs
for millions world wide!

34. Marlene E. Haffner, MD, MPH
President & CEO
11616 Danville Drive
Rockville, Maryland 20852
mhaffner3@verizon.net
www.mhaffner.com
301 984 5729 - office
301 641 4268 - cell
301 984 2272 - FAX