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Orphan Drugs
1. Orphan Drugs
Regulatory Affairs – Humber College
Huiyan Zha
Jaideep Patel
Maggie Adamczenko
Rosa Hernandez
Subhadeep Chakrabarti
Tahmina Afzali
Zaki Abu Rabi
2. Orphan Drugs
Target: Regulatory Affairs professionals
General definition: Drugs for rare diseases that
usually do not have a commercial appeal.
Overview of the following markets:
US
EU
Australia
Canada
4. The Orphan Drug Act (ODA)
• Decade prior to 1983 – only ~1 drug/year developed by
pharmaceutical sponsors
Kefauver Harris Amendment in 1962 Increased the costs of new drug development
Pharmaceutical companies responded by focusing on drugs for common diseases
• Rare disease drug development needed to be promoted
National Organization for Rare Disorders
• The Orphan Drug Act signed into law on Jan. 4, 1983
Aimed to facilitate development of drugs for rare diseases
• Affect < 200, 000 people in USA
• Affect > 200,000 persons but are not expected to recover the costs of developing and marketing a
treatment drug
5. What are the Incentives for Orphan-Drug
Designation?
• 7-year marketing exclusivity
• Tax credits (up to 50% of clinical development costs)
• Exemption/Waiver of application (filing) fees
• Office of Orphan Product Development (OOPD) assistance during the
development process
• Administers grant programs for clinical research
6. Is the Orphan Drug Act a Success?
• 500+ drugs and biologic products marketed for rare diseases
since 1983
• < 10 such products marketed between 1973 to 1983
• The Orphan Grants Program has brought 45+ products to
marketing approval
9. EU Orphan Drug Legislation
One of the founding principles of European Regulation 141/2000 on orphan medicines is:
“Patients suffering from rare conditions should be entitled to the same quality of treatment as other
patients”
• Rare disease: no more than 5 in 10,000 people in EU
• It must be used for treatment, prevention or diagnosis of diseases which are life-threatening or
chronically debilitating.
• There is no acceptable method of diagnosis, prevention or treatment of the condition. If that kind of
medicine exists, it must be of significant benefit of the existing method.
• Adopted on December 16th, 1999
• It established the basis for development, marketing and use of orphan medicines in EU.
• New EU procedure for designation of orphan medicine has been set up.
• Fortify incentives for development and market placement of orphan medicines.
• Committee for Orphan Medicinal Products (COMP) has been established as governing body.
10. • Assistance in development process (protocol assistance, scientific advice,
etc.).
• Fee reductions from regulatory agencies (for marketing-authorisation
application).
• 10 years of market exclusivity (protection from competition after it is
released on the market)
EU Incentives for Developing and Marketing
Orphan Drugs
11. • Development of rare drugs.
• Significant increase in rare medicine applications (more than 150 a year).
• The European Commission authorised 122 orphan medicines and designated 1362 products
as orphan medicinal products so far.
• Special aid for research designated for small and medium-sized enterprises.
• Access to rare medicines for patients who otherwise would not receive any treatment.
• Possible problems:
• The price of orphan medicines in many EU member states presents a problem for reimbursement bodies due
to their cost-benefit ratio. Many drugs, though approved, are not available in all member countries due to a
high price.
Orphan medicines legislation has enabled:
13. TGA & Orphan Drugs
• TGA is the regulatory agency for health/medical products in
Australia
• Responsible for orphan drugs
• Orphan drugs are defined as (16H of Therapeutic Goods Regulation):
• Drugs intended for rare diseases
• Drugs which are not economical to supply in Australia (for rare disease
or any other conditions)
• Drugs which have not been considered unsafe by international
regulatory agencies such as FDA, Health Canada or EMA
14. What does it mean?
• Orphan drugs are waived the evaluation and registration fees by
TGA
• Must receive ‘orphan’ status prior to applying for evaluation &
registration
• Status depends on drug, dose form & target disease
• Rare disease: 2000 or less patients in Australia at a given time
15. Pros and Cons
• PROs:
• Encourages availability of these drugs in a small (~21 million
population) market
• Simple procedure: only waiving of regulatory fees
• No effect on R&D, as Australia has limited pharma industry
• CONs:
• Too stringent criteria for ‘rare’ disease: 0.88 per 10,000 instead of
5 per 10,000 (EMA, Swissmedic)
• No incentive to develop local industry in Australia
16. Who benefits?
• Patients:
• Sufferers from ‘rare’ diseases
• About half (48%) are anti-cancer and haematological drugs
• Companies:
• Multi-national “big pharma” disproportionately over-represented
• Small number of biotechnology companies
• Evaluation:
• Recently concluded consultation for changes to orphan drugs
regulation: Ideas (lowering threshold for ‘rare’ conditions, reduced
fees, status quo, or abolition?)
18. Regulatory Trends
• In 1997, Health Canada rejected Orphan Drug Policy.
• Health Canada’s decision was not sufficient for Canadian patients.
• In 2012, Health Canada’s “Orphan Drug Framework” draft established.
• Health Canada’s draft definition of a rare disease is one that affects fewer
than 5 in 10,000 persons in Canada.
• In March of 2016, the Canadian Agency for Drugs and Technologies in
Health (CADTH) published their own recommendation framework.
19. The HC framework includes 6 key features:
• Designation: Regulations will include orphan drug designation criteria and processes.
• Clinical Trials: Trials will be carried out under the existing clinical trial framework (Part C, Div. 5 of FDR).
• Scientific Recommendation: Companies holding an orphan drug designation can request scientific advice
from HC for help in designing and implementing clinical trials.
• Post-Market Plan: An application for an orphan drug must include a post-market plan according to the
drug’s benefits, risks, and uncertainties.
• International Collaboration: The proposed framework will be harmonized with existing frameworks in
other jurisdictions (US and EU) to ensure ease of collaboration.
• Patient Collaboration: Patient input at the designation and the
drug review stage will be required.
20. Regulatory Proposal
Framework Administrative
Authority
Grants
for R&D
Prevalence
for ‘orphan drug’
designation
Market
Exclusivity
Tax
Credit
Reconsideration
on applications
for orphan
designation
Technical
Assistance
Accelerated
Marketing
Initial Draft Health
Canada
CIHR Substantial
benefit to patient
vs. existing
therapy
8 years No Yes Yes Yes
21. • Limited number of clinical studies.
• Small sample sizes (e.g. due to rare disease that affects a relatively small number of
patients (incidence of fewer than 5 in 10,000, but typically closer to 1 in 100,000).
• Short study durations or follow-up.
• Inability to distinguish disease severity in heterogeneous manifested rare diseases.
• Insufficient evidence on meaningful clinical end points.
• Less stringent statistical analyses.
Clinical Data for Orphan Drugs: Proposed
Modification
22. Patient Access to Orphan Drugs
• Improving early detection and prevention
• Providing timely, equitable and evidence-informed care
• Enhancing community support
• Providing sustainable access to promising therapies
• Promoting innovative research
23. Fixed Pricing
1. Reference pricing
2. Prices set at the discretion of governmental and
regulatory bodies.
26. Potential Limitations of the Draft
• Canada’s Orphan Drug Framework draft is similar to the implemented frameworks of the US, EU
and Australia, so Canada will likely face similar challenges.
• Population prevalence definitions of “rare disease” are ambiguous and quickly losing meaning –
Canada should consider identifying target diseases for orphan drug designation based on unmet
patient need.
• Canada is a relatively small market, and this should be factored into local policy development –
Canada may benefit from allowing companies to earn relatively greater profits on orphan drugs as
compared to other jurisdictions so as to encourage market entry.
• To encourage R&D of new orphan drugs, judicious provision of intellectual property protections is
imperative.
• Finally, the current draft should include a plan to support equitable reimbursement of orphan drugs,
or patients in some provinces may not be able to access orphan drugs even if approved for the
Canadian marketplace.
27. Summary
Legislation and Provisions US (FDA) EU (EMA) Australia (TGA) Canada (proposed and existing)
Orphan Drug Legislation or Policy Orphan Drug Act 1983 Regulation on Orphan Medicinal
Products 1999
Orphan Drug Program1997 Orphan Drug Framework 2012
Marketing Exclusivity Period 7 yearsa
10 years (extended by 2 years for
medicines that also comply with required
pediatric investigations)
No 8 years
Accelerated Evaluation Availability Yes Yes Yes Yes
Application or Other Regulatory Fee
Reductions or Waivers
Yes Yes Yes Yes
Scientific Advice (Research Protocols,
Technical Assistance, etc.)
Yes Yes Yes Yes
Tax Incentives 50% tax credits for
clinical research
costs
Tax credits developed by each member
state
No No
28. Conclusions
• Health Canada’s Orphan Drug Framework will facilitate orphan drug regulatory approval, attract more such
drugs to the Canadian market, accelerate market authorization, and align Canadian regulatory activities with
those of international partners.
• By harmonizing with US and EU criteria, Canadians will benefit from having drugs registered at the same
time (vs. up to 6 years later than in the US or EU), opening the way for inclusion in clinical trials .
However:
• ODF is still considered a “Forward Regulatory Plan for 2016-2018” to amend the Food and Drug Regulations.
• Without the ODF, Canada is simply a bystander and not a contributor to the research and the dialogue on
appropriate sustainable access to orphan drugs.
Public consultation opportunities will be available to all Canadians – expected to take place by 2017.
But is there anything we can do in the interim?
You can show your support for Canada’s Orphan Drug Regulatory Framework!
The Canadian Organization for Rare Disorders (CORD) has created a “Template Letter to your Local MP”
(which can be e-mailed or mailed), and is accessible at: https://www.raredisorders.ca/show-your-support-for-
the-orphan-drug-regulatory-framework-send-a-template-letter-to-your-local-mp/
30. References
Anthony K Hall, Marilyn R Carlson. (2014) The current status of orphan drug development in Europe and the US. Intractable &
Rare Diseases Research. 3(1):1-7. Retrieved from: www.ncbi.nlm.nih.gov/pmc/articles/PMC4204542/
CADTH. (2016, February). Drugs for Rare Diseases: Evolving Trends in Regulatory and Health Technology Assessment
Perspectives. CADTH Environmental Scan. Version: 2.0. Issue Number: 42 . Retrieved from: https://www.cadth.ca/drugs-rare-
diseases-evolving-trends-regulatory-and-health-technology-assessment-perspectives
CCR. (2016). THERAPEUTIC GOODS REGULATIONS 1990 - REG 16H. Retrieved from:
www.austlii.edu.au/au/legis/cth/consol_reg/tgr1990300/s16h.html
de Leon, Ezra. (2016, January 7). Orphan Drugs in Canada. DCT Regulatory Affairs Consultants. Retrieved from:
http://regulatoryaffairs-consultants.ca/orphan-drugs/
EMA. (1999, December 16). REGULATION (EC) No 141/2000 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16
December 1999 on orphan medicinal products. Retrieved from: http://ec.europa.eu/health/files/eudralex/vol-
1/reg_2000_141/reg_2000_141_en.pdf
EMA. (2016). Medicines for rare diseases. Retrieved from:
www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000034.jsp&mid=WC0b01ac05800
2d4eb
31. References
EMA. (2016). Legal background: orphan designation. Retrieved from:
www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000552.jsp&mid=WC0b01ac058061ec
b7
Health Canada. (30 September 2016). Forward Regulatory Plan: 2016-2018. Retrieved from: www.hc-sc.gc.ca/ahc-
asc/legislation/acts-reg-lois/frp-ppr/2016-2018/index-eng.php
Innomar. (2016, May 18). InnomarLive Recap: A Comprehensive Look at Rare Disease in Canada. Innomar Strategies.
Retrieved from: http://www.innomar-strategies.com/news-and-events/detail/innomarlive-rare-disease-recap
Karst, Kurt. R. (2015, February 15). The 2014 Numbers Are In: FDA's Orphan Drug Program Shatters Records. Retrieved from:
www.fdalawblog.net/fda_law_blog_hyman_phelps/2015/02/the-2014-numbers-are-in-fdas-orphan-drug-program-shatters-
records.html
McKesson. (2016). Towards a New Way of Evaluating Orphan Drugs at CADTH. White Paper. McKesson Canada 2016.
Retrieved from: https://www.mckesson.ca/documents/1222016/1224126/Orphan+Drug_white+paper.pdf/73d8f7a5-20df-
47b7-9eef-d20fe95d6e1b
32. References
TGA. (2016, March 6). Applications for orphan drug designation. Retrieved from: www.tga.gov.au/book-page/how-apply-
orphan-drug-designation
TGA. (2015, July 28). Consultation: Orphan drugs program. Retrieved from: www.tga.gov.au/consultation/consultation-
orphan-drugs-program
Thomas, M. (n.d.). (2016, October 11). The Orphan Drug Act and the Development of Products for Rare Diseases. Retrieved
from: https://rarediseases.info.nih.gov/files/fda orphan drugs.pdf
Todd Gammie, Christine Y. Lu, Zaheer Ud-Din Babar. (2015, October 9). Access to Orphan Drugs: A Comprehensive Review of
Legislations, Regulations and Policies in 35 Countries. PLOS ONE. Retrieved from:
https://dash.harvard.edu/bitstream/handle/1/23473978/4599885.pdf?sequence=1
Hinweis der Redaktion
What about medical Devices?
Humanitarian Device Exemption (HDE) Program
Humanitarian Use Device (HUD) = Device treating a disease affecting < 4,000 in the US per year
44 HDE approvals
T
Disease must not affect more than 5 in 10,000 people in EU or invested funds are most likely not to be regained to justify the investment.
In 1997, Health Canada specifically rejected the need for a Canadian Orphan Drug Policy, citing that “means” to assure access to drugs for rare diseases were available to manufacturers within existing legislation. --> Canada backs its decision by stating that 60% of US Orphan Drugs are approved in Canada.
Canada’s Orphan Drug Policy. (n.d.). Retrieved October 10, 2016, from https://www.raredisorders.ca/our-work/
Unfortunately, these mechanisms are not sufficient to insure that Canadian patients with rare diseases will have access to critical and life-saving medicines. There is no motivation for manufacturers to seek market approval and to make these drugs available in Canada. Since Canada does not offer competitive R&D incentives, there will be no Canadian-based pharmaceutical and biotechnological research and development for domestic use or export.
Canada’s Orphan Drug Policy. (n.d.). Retrieved October 10, 2016, from https://www.raredisorders.ca/our-work/
The Canadian Organization for Rare Disorders (CORD) believes that Canada needs a rare disease strategy to facilitate and better coordinate the efforts of governments and stakeholders involved in addressing the current challenges and ensuring that all people with rare disorders across the country can enjoy the same timely and quality health and social care as patients with more common diseases.
CANADA’S RARE DISEASE STRATEGY. (n.d.). Retrieved October 10, 2016, from https://www.raredisorders.ca/our-work/
“A drug intended for the diagnosis, treatment, mitigation or prevention of a life- threatening, seriously debilitating, or serious and chronic disease or condition affecting not more than five in ten thousand persons in Canada, and the drug is not currently authorized by the Minister or if currently authorized, it will provide a potentially substantial benefit for the patient distinguishable from the existing therapy.”
Drugs for Rare Diseases: Evolving Trends in Regulatory and Health Technology Assessment Perspectives. (n.d.). Retrieved October 10, 2016, from https://www.cadth.ca/drugs-rare-diseases-evolving-trends-regulatory-and-health-technology-assessment-perspectives
The format and information for market authorization is to be the same as for a New Drug Submission for other drugs, but will include built-in flexibility for small clinical trials. The only additional information required is a copy of the Orphan Drug Designation, information on its designation in other countries (if applicable), and a post-market plan.
these sources of uncertainty have, in the past, been prominent
critical points in CDEC reviews of rare disease drugs and have played
a large role in negative reimbursement decisions. While the new framework lists factors that contribute to uncertainty
of clinical benefit, no changes to CADTH’s policies on health
economic evaluations are mentioned. This absence is significant,
because in many cases orphan drugs have not been recommended
for reimbursement by CADTH because of unacceptable costeffectiveness
ratios.
The Canadian Organization for Rare Disorders (CORD) has released Canada’s Rare Disease Strategy, developed with experts from every sector.
Improving early detection and prevention
Adopt a national approach to newborn screening
Implement early detection and preventive services across Canada
Providing timely, equitable and evidence-informed care
Improve education and capacity of healthcare providers related to rare diseases, including genetic counsellors
Enhancing community support
Rare disease-specific patient organizations, as well as CORD and the RQMO, should be adequately funded to achieve their missions, which include involvement in research initiatives, knowledge translation, policy development, education, engagement and support initiatives for patients
Increase resources to optimize the utility of Orphanet for all stakeholders
Providing sustainable access to promising therapies
Implement a regulatory framework for orphan drug
Explore adaptive clinical trial designs for market authorization and post-market phases of therapies
Enhance and formalize the role of patients in the market authorization process and post-market evidence-generation and provide resources to support the participation of rare disease patient groups in this process
Promoting innovative research
Provide dedicated and increased funding for rare disease research and the Centres of Excellence on rare diseases
Establish a new Canadian Partnership for Rare Diseases to help coordinate a national rare disease research agenda and Centres of Excellence on rare diseases, among other actions recommended throughout this strategy
Canada's Rare Disease Strategy. (2015). Retrieved October 11, 2016, from https://www.raredisorders.ca/our-work/
1. whereby a country compares the price requested by the manufacturer with the price in other countries
2. These prices remain fixed as the respective agency will ‘fix’ the price at a level it determines optimal. This included measures such as “cost plus” pricing set at the cost of research and development plus a profit percentage.
Paris, Valérie, and Élizabeth Docteur. "Pharmaceutical pricing and reimbursement policies in Canada." (2007).
Paris, Valérie, and Élizabeth Docteur. "Pharmaceutical pricing and reimbursement policies in Canada." (2007).
Canada should capitalize on learning from other countries’ experiences.
Canada should consider moving to coordinate the targeting of incentives to those orphan drugs most likely to be reimbursed by payers.
Companies are not motivated to conduct clinical trials in Canada.
Unlike countries such as the US, Canada hasn’t established guidelines for clinical trials or approval timelines for rare disease treatments, which can make companies reluctant to seek drug approvals here.
Even when an orphan drug is discovered in Canada (often with Canadian research dollars), the discovery is then transferred for further development to a company in the US or EU, where incentives are designated.
