The document discusses orphan drugs and the need for orphan drug development. It defines orphan drugs as medicines developed to treat rare diseases affecting fewer than 5 in 10,000 people. It describes orphan drug policies in the US, EU, Japan and Australia which provide incentives like market exclusivity, tax credits and protocol assistance to encourage orphan drug development. It discusses hurdles to access orphan drugs in India like high prices and lack of formal incentives. It summarizes recent orphan drug approvals in the US and top selling orphan drugs worldwide. It highlights the need for policies and initiatives in India to encourage orphan drug development and ensure affordable access.

1. Presented By: Kharat Pratik Kondu
Reg. No: PE/2019/313
Subject Code: GE-511
Department of Pharmaceutics
12-Mar-20 1
Department of Pharmaceuticals, Ministry of Chemicals & Fertilizers, Govt. of India.
राष्ट्रीय औषधीय शिक्षा एवं अनुसंधान संस्थान
National Institute of Pharmaceutical Education and Research, Hyderabad

2. 12-Mar-20 2
Introduction
Orphan vs Essential drugs
Need for Orphan Drug development
Orphan Drug Act
Impact of Act
Orphan Drug designation process
Indian perspective
Recently approved drug in US
Top selling Orphan Drugs
Marketed Orphan Drugs
Summary

3. 12-Mar-20 3
The Orphan Drug is a medicinal product that is developed to treat, diagnose or prevent
a specific rare disease.
The so-called ‘Orphan Drugs' are intended to treat diseases so rare that sponsors are
reluctant to develop them under usual marketing conditions.
 Orphan drugs :
 Rare diseases :
Diseases that manifest in patient populations representing at the maximum 6-8% of the
world population are defined as “Rare Diseases” or “Orphan Diseases”.
NO UNIVERSAL DEFINITION
Franco P. et al., Drug Discovery Today, 2013;(18):163-72.

4. 12-Mar-20 4
Country, region or
organization
Definition
WHO A disease or a condition affecting 0.65-1 in 1000 inhabitant
EU A life-threatening or chronically debilitating condition affecting not
more than 5 in 10,000 persons in the community; or life-
threatening, seriously debilitating or serious chronic condition in
EU and without incentives the Sponsor would unable develop the
medicine; and there are no other satisfactory method of
diagnostic, prevention or treatment of the condition
US A disease or a condition, which affects fewer than 2,00,000
patients in US
JAPAN A disease that affects fewer than 50,000 patients in JAPAN
AUSTRALIA A disease that affects fewer than 2000 patients per year
Franco P. et al., Drug Discovery Today, 2013;(18):163-72.
WHO- World Health Organization, EU-European Union, US- United States

5. Country , region or
organization
Prevalence per
10000 of
population
WHO 6.5-10
US 6.4
JAPAN 3.9
CANADA 1
EUROPE 5
INDIA -
12-Mar-20 5
 For India there is no standard definition
 As per ORDI (Organization for Rare Diseases in India) disease to be defined as rare if it
affects 1 in 5,000 people or less
https://ordindia.org/about-rd/rare-disease-definition/ (Accessed on 18 November 2019)
Franco P. et al., Drug Discovery Today, 2013;(18):163-72.

6. 12-Mar-20 6Reddy DS, et al., Asian Journal of Pharmaceutics, 2014;8(2).130-32.
Drug-driven
Essential
Drugs
Orphan Drugs
Individual patient health
first
Disease-driven
Public health first

7. 12-Mar-20 7
Orphan Drug candidate Non Orphan Drug
candidate
Special policies in place
since
1983 in the US, 2000 EU, etc. 1977 worldwide
Primary focus Individual patient: even a
single patient warrants all
possible treatments
Public health: bringing
effective medicines to
as many patients as
possible
Criteria Disease driven Drug driven
Policies aim to Provide new medicines to
untreatable patients
Provide new medicines
to patients with
established treatments
Initiated by US, EU, JAPAN, AUSTRALIA WHO
http://www.appliedclinicaltrialsonline.com/orphan-drugs-market-overview-and-country-
specific-analysis (Accessed on 18 November2019)
Reddy DS, et al., Asian Journal of Pharmaceutics, 2014;8(2).130-32.

8.  Rarity of the particular disease itself limit drug development
 Right to medicine
12-Mar-20 8Franco P. et al., Drug Discovery Today, 2013;(18):163-72.

9. 12-Mar-20 9
21 CFR Part 316
https://www.fda.gov/industry/designating-orphan-product-drugs-and-biological-products/e-cfr-21-part-316-orphan-drug-orphan-
drug-act-1983 (Accessed on 21 November 2019)
 USA is the first country
 Enact Orphan Drug Act (ODA) on January 4th,1983
 Initially, Orphan Drug status was applied to non-profitable drugs
 Original ODA allowed sponsors to apply for orphan drug
designation even after FDA marketing application
 Orphan Drug Amendment of 1988 restricts sponsor to apply for
Orphan Drug designation after submission of a marketing
application

10. 12-Mar-20 10Franco P. et al., Drug Discovery Today, 2013;(18):163-72.

11. 12-Mar-20 11
USA JAPAN AUSTRALIA EU
Legal framework ODA (1983) Orphan drug
regulation (1993)
Orphan drug
policy (1997)
Regulation (CE) no.
141/2000 (2000)
Administration
involved
FDA/OOPD MHLW/OPSR TGA EMEA/COMP
Market exclusivity 7 years 10 years 5 years 10 years
Tax credits 50% of clinical
costs
6% of both clinical
and non clinical
cost
No Managed by
member states
Protocol assistance Yes Yes Yes Yes
Accelerated review Yes Yes Yes Yes
Application fee
waiver
Yes No Yes Reduced fee
FDA : Food and Drug Administration,
OOPD: Office of Orphan Products Development,
EMEA: European Medicines Agency,
COMP: Committee for Orphan Medicinal Products,
MHLW: Ministry of Health, Labor and Welfare,
OPSR: Organization for Pharmaceutical Safety and Research,
TGA: Therapeutic Goods Administration.
 Comparative incentives describe in the orphan drug legislation
adopted by different regions.
Reddy DS, et al., Asian Journal of Pharmaceutics, 2014;8(2).130-32.

12. Prior to passing the Orphan drug policies, only 10 in US and 8 in EU treatments for rare diseases had
been developed possibly due to the
12-Mar-20 12Attwood MM, et al., Trends in Pharmacological Sciences, 2018 ;39(6):525-35.

13. 2
38 44
33
54
6975 87 81
57 6561 58 58 56 69 79 72 81
66
100
136
127
155
124
168173
203 204 201
273
297
360
335
479
337
300+
0 2 6 5 8 9 11 10 12 14 13 10 11
25 18 20 20 14 6 13 12 14 20 24 16 17 20 15
26 26 33
51 49 40
81
94
69+
0
100
200
300
400
500
600
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
2019
Number of Orphan Drug designation and approval in US
No of designation
No of approval
Years
12-Mar-20
13
https://www.accessdata.fda.gov/scripts/opdlisting/oopd/ (Accessed on 23 November 2019)
NumberofOrphanDrugdesignation/approval

14. 12-Mar-20 14

15. 12-Mar-20 15
USA and EU orphan drug
designation every year
https://www.wns.com/insights/articles/articledetail/458/pharma-ci-strategies---orphan-drug-development---
wns-article (Accessed on 26 November 2019)
Year

16. Timing of requests for Orphan Drug designation
12-Mar-20 16
Clinical development
CAN SUBMIT DESIGNATION
REQUEST
SUBMISSION
FOR
MARKETING
APPROVAL
https://www.ecfr.gov/cgi-bin/text
idx?SID=c752b78870bf3f4fa65c13b63b446538&mc=true&node=sp21.5.316.c&rgn=div6
(Accessed on 18 November 2019)
Pre-clinical
development

17. Amendment to Orphan
Drug designation,
if any
If positive
response
12-Mar-20 17
Request for Orphan Drug designation
Verification of Orphan Drug status (90days)
Submission of clinical
data
Unable to
respondDeficiency letters and granting
Orphan Drug designation
(Has to respond within 1 year)
Refusal to grant
Orphan Drug
designation
Granting
Orphan Drug
designation
Annual reports of
holder of Orphan
Drug designation Approve for Marketing
https://www.ecfr.gov/cgi-bin/text
idx?SID=c752b78870bf3f4fa65c13b63b446538&mc=true&node=sp21.5.316.c&rgn=div6
(Accessed on 18 November 2019)

18.  About 6000-8000 rare diseases, mostly genetic in nature have been identified
eg. Addison’s disease
Ichthyosis retinitis pigmentosa
 400+ FDA and 80+ EMA approved Orphan Drugs are available in India and world-wide
 Most of them are either not accessible or are unaffordable
 No formal incentives are provided by Govt.
12-Mar-20 18Reddy DS, et al., Asian Journal of Pharmaceutics, 2014;8(2).130-32.

19.  Central Drugs Standard Control Organization (CDSCO)
- July 2014 notice regarding waiver of clinical trials for
approval of new drug in Indian population
- For drugs which are already approved outside India
- Drugs Controller General of India suggested custom duty exemption
 Indian Council of Medical Research(ICMR) initiative
- Proposed “Indian rare disease registry”
 Non-govt. organization initiative
- Organization for Rare Disease in India (ORDI)
12-Mar-20 19Kumar H, et al., Indian Journal of Pharmacology. 2017 ;49(4):267.
 Different initiatives in India

20. Awareness
Affordability and Accessibility (import and distribution) of orphan
drugs in India
High prices of orphan drugs in India
12-Mar-20 20Reddy DS, et al., Asian Journal of Pharmaceutics, 2014;8(2).130-32.
 Hurdles to access orphan drugs in India

21.  Recent Orphan Drug review at the FDA
Acalabrutinib for treatment of Chronic lymphocytic leukemia (CLL)
It is a type of cancer in which the bone marrow makes too many lymphocytes.
Also,
Approved for - Mantle cell lymphoma
Designated for - Waldenstrom macroglobulinemia
12-Mar-20 21
https://www.accessdata.fda.gov/scripts/opdlisting/oopd/ (Accessed on 22 November 2019)

22. Generic Name Acalabrutinib
Trade Name N/A
Date Designated 05/13/2015
Orphan Designation
Treatment of chronic lymphocytic leukemia
(CLL)
Orphan Designation Status Designated/Approved
Marketing Approval Date 11/21/2019
Approved Labeled
Indication
Acalabrutinib is indicated for the treatment of
adult patients with chronic lymphocytic leukemia
(CLL)
Exclusivity End Date To be declared
Sponsor
Acerta Pharma,
South San Francisco, California 94080
USA
12-Mar-20 22https://www.accessdata.fda.gov/scripts/opdlisting/oopd/ (Accessed on 22 November 2019)

23. Generic name: NRC-AN-019
Trade name: N/a
Date designated: 03/18/2011
Orphan designation: Treatment of glioma
Orphan designation status: Designated
FDA orphan approval
status
Not FDA approved
Marketing approval date N/a
Exclusivity end date N/a
Sponsor:
NATCO pharma limited,
Hyderbad 500033 India
12-Mar-20 23https://www.accessdata.fda.gov/scripts/opdlisting/oopd/ (Accessed on 22 November 2019)
 First drug designated as orphan drug by USFDA
 The drug was developed by NATCO Pharma.

24. 12-Mar-20 24
http://www.pharmafile.com/news/503622/trend-rare-disease-cancer-
drugs-will-drive-pharma-ma-s-growth (Accessed on 28 November 2019)
Drug Use Company Sale forecast to 2020
Revlimid®
(lenalidomide)
Multiple myeloma (bone
marrow cancer)
Celgene $10.05 billion
Opdivio®
(nivolumab)
Lung cancer BMS $8.19 billion
Soliris®
(Eculizumab)
Paroxysmal nocturnal
hemoglobinuria (PNH)
Alexion
Pharma
$5.41 billion
Keytruda®
(Pembrolizumab)
Skin cancer Merck & Co $5.29 billion
Rituxan®
(Rituximab)
Rheumatoid arthritis Roche $5.11 billion
Tsigna®
(Nilotinib)
Blood cancer Novartis $2.33 billion

25. 12-Mar-20 25
 Elaprase (Idursulfase)
• Dose - 0.5mg/kg
• By intravenous infusion
• For the treatment of Hunter’s syndrome
• Developed by Shire Human Genetic
Therapies
 Cerezyme (Imiglucerase)
• Dose - 2.5 units/kg IV infused over 1-2 hr 3
times per week
• By intravenous infusion
• For treatment of Type 1 Gaucher disease
• Developed by manufactured by Genzyme
Corporation
cerezyme
$200,000 a year
http://www.appliedclinicaltrialsonline.com/orphan-drugs-big-potential-
small-disease-states (Accessed on 27 November 2019)

26.  There is increased development of Orphan Drugs in US and various
regions due to enactment of Orphan Drug related legislations
 Strong policies and initiatives are needed from government of India to
encourage development of Orphan Drugs
 The approved Orphan Drug should have easy & affordable access in
India
12-Mar-20 26

27. 12-Mar-20 27
“There is a need for a coordinated effort on
national level for more research and
understanding of rare diseases in the country.
To cure these rare diseases, the pharma
industry must focus on inventing
new medicines ”
– Dr. APJ Abdul Kalam
In a conference on “Raising awareness on
rare diseases” while addressing the
students of 4th convocation at NIPER
HYDERABAD

28.  Franco P. Orphan drugs: the regulatory environment. Drug Discovery Today. 2013;18(3-4):163-
72.
 Seoane-Vazquez E, Rodriguez-Monguio R, Szeinbach SL, Visaria J. Incentives for orphan drug
research and development in the United States. Orphanet Journal of Rare Diseases.
2008;3(1):33.
 Reddy DS, Pramodkumar TM, Reddy Y, Sirisha K. Orphan regulations for orphan drug
development in India. Asian Journal of Pharmaceutics;2014;8(2).130-32.
 https://ordindia.org/about-rd/rare-disease-definition/ (Accessed on 18 November 2019)
 http://www.appliedclinicaltrialsonline.com/orphan-drugs-market-overview-and-country-specific-
analysis (Accessed on 18 November 2019)
 https://www.fda.gov/industry/designating-orphan-product-drugs-and-biological-products/e-cfr-
21-part-316-orphan-drug-orphan-drug-act-1983 (Accessed on 21 November 2019)
 https://www.accessdata.fda.gov/scripts/opdlisting/oopd/ (Accessed on 23 November 2019)
 Attwood MM, Rask-Andersen M, Schiöth HB. Orphan drugs and their impact on pharmaceutical
development. Trends in pharmacological sciences. 2018 ;39(6):525-35.
 https://www.ecfr.gov/cgi-bin/text
idx?SID=c752b78870bf3f4fa65c13b63b446538&mc=true&node=sp21.5.316.c&rgn=div6
(Accessed on November 2019)
12-Mar-20 28

29. 29

30. 12-Mar-20 30

31.  Limits between development phases may not be clear-cut
 Sometimes approval may be granted without a typical clinical trial
programe
 Minimum exposure requested for conventional drugs according to
international regulations (ICH E1A)
 Does not apply to orphan drugs
 It is not defined what is expected
12-Mar-20 31
Tankovic, G. et al., Designing robust clinical trials for orphan drugs.Orphan Drugs. 2013; 187–246.