This document discusses orphan diseases, orphan drugs, and regulatory aspects of orphan drugs in the US and Europe. It defines orphan diseases as those affecting fewer than 200,000 people in the US or 1 in 2000 people in Europe. Despite affecting a small percentage of the population, over 55 million people in the US and EU have orphan diseases. The document outlines regulations in the US and EU to incentivize development of orphan drugs, including market exclusivity periods. Key incentives include clinical trial cost subsidies and expedited FDA review in the US, as well as free orphan designation review by the EMA in Europe.

1. ORPHAN DISEASES,ORPHAN DRUGS AND
REGULATORYASPECTS OF ORPHAN DRUGS IN
US AND EUROPE

2. ORPHAN DISEASES
 An orphan disease is defined as a condition
that affects fewer than 200,000 people
nationwide. This includes diseases as
familiar as cystic fibrosis, Lou Gehrig's
disease, and Tourette's syndrome, and as
unfamiliar as Hamburger disease, Job
syndrome, and acromegaly, or "gigantism”.
A disease or disorder is defined as rare in Europe when it
affects fewer than 1 in 2000. A disease or disorder is defined
as rare in the USA when it affects fewer than 200,000
Americans or about 1 in 1500 Americans.
According to the definition by the World Health Organization
(WHO), an orphan disease is an illness or condition that occurs
from 0.65 to 1 case per 1000 population, with a prevalence from
6.5 to 10 cases per 10.000 residents.

3. Annually, approximately 250 new orphan diseases are identified
Despite the fact that orphan diseases affect a small portion of the
world population, it is estimated that over 55 million people suffer
from orphan diseases at the level of the United States (USA) and
European Union (EU).
 In the USA there are about 25 million people who suffer from an
orphan disease, while at European level about 30 million people
are registered with orphan diseases, meaning that orphan
diseases affect 6% to 8% of the population at European level .
The large part of orphan diseases (about 50%) appear during
early childhood. Approximately 80% of the known orphan diseases
have been identified as genetic in nature affecting between 3%
and 4% of the newborns.

4. EXAMPLES OF RARE DISEASES
Gaucher disease
 Gaucher disease is a rare genetic disorder
characterized by the deposition of
glucocerebroside in cells of the macrophage-
monocyte system. The disorder results from
the deficiency of the enzyme
glucocerebrosidase.The prevalence of
Gaucher disease is around 2 in 100 000.
 Gaucher disease is the result of a buildup of
certain fatty substances in certain organs,
particularly your spleen and liver.
An enzyme that breaks down these fatty substances doesn't work
properly in people with Gaucher disease.Treatment often includes
enzyme replacement therapy.
This causes these organs to enlarge and can affect their function.

5. Von Hippel-Lindau (VHL)
Von Hippel-Lindau disease (VHL) is said to
affect one in 35,000 people. It is an extremely
rare genetic condition that is characterized
by the growth of tumors in different parts of
the body. Many of the tumors will grow
within the central nervous system and are
often benign, but are made of blood vessels.
Medically known as hemangioblastomas, these tumors can
start to grow in the retina, the brain, and the spinal cord.
Different tumors are also known to grow on the pancreas,
adrenal glands, and kidneys. If left untreated, the disease can
cause strokes, heart attacks, and cardiovascular disease.

6. Microcephaly
Microcephaly is a very rare condition that is
noticeable immediately at birth, and sometimes
even before. It affects 1 in every 666,666 in the
U.S. With microcephaly, the brain is unable to
develop properly, or in some cases ceases to
grow at all, while the baby is still in the womb.
Many believe that the disease is caused by
exposure to harmful substances while in the
womb, exposure to radiation, or genetic
problems.
The disease is usually paired with Down’s syndrome. Those
who have microcephaly are usually mentally retarded and will
have issues with hyperactivity, dwarfism, seizures, balance
issues, speech and motor problems, as well as others.

7. ORPHAN DRUGS
Orphan drugs are medicines or vaccines intended to treat, prevent or diagnose
a rare disease. Examples of rare diseases include genetic diseases, rare
cancers, infectious tropic diseases and degenerative diseases.
Type Detail Expected profits Available
medication
I Little / no
commercial benefit
Poor Inadequate
II Commercial
benefit
Good to excellent Inadequate
III For rare disease
that can currently
be treated
Variable Adequate
IV Unprofitable for a
common disease
Poor Inadequate
V Orphan for both
rare and common
diseases
Variable Variable
Categories of Orphan Drugs

8. TOP 20 ORPHAN DRUGS BY 2018
Rituxan Rebif
Revlimid Kalydeco
Soliris Jakavi
Afinitor Sutent
Tasigna Kyprolis
Velcade Kogenate
Avonex NovoSeven
Alimta Nexavar
Yervoy Copaxone
Sprycel Ibrutinib

9. ORPHAN DRUG REGULATION IN US AND EUROPE
ORPHAN DRUG REGULATION IN US
 The legal status had been given to the orphan drugs in the USA
on 4 January 1983 with the passing of an act called the Orphan
Drug Act.
 The Orphan Drug Act is passed to stimulate the development of
drugs and biological products for the treatment of rare diseases.
 The ODA includes specific regulations that were developed to
promote R&D investment in orphan drugs. The ODA has
several parts but its main purpose is to reduce costs and
increase the returns to orphan drug production. The ODA
allows drug sponsors to obtain recommendations from the
FDA pertaining to the clinical and nonclinical trials of a drug
before its approval.

10. Additionally, the ODA allows the FDA to expedite orphan drug
designation approvals over other drugs, reducing the development
time. The ODA also established a grant program in which subsidies
are given to drug manufacturers, to a total of about $30,000,000
each fiscal year.This helps cover some of the costs of clinical trials.
This act delivers incentives to pharmaceutical companies to
develop drugs which are lifesaving and often essential for the
patients suffering from rare diseases but had a marginal
commercial profit on investment. The Orphan Drug Act is codified
in 21 CFR Part 316.

11. ORPHAN DRUG REGULATION IN EUROPE
In 2000, the European Union (EU) has enacted similar legislation,
Regulation(EC) No 141/2000, which refers to drugs developed to
treat rare diseases to as "orphan medicinal products". The EU's
legislation is administered by the Committee on Orphan Medicinal
Products of the European Medicines Agency (EMA).
The first step towards making regulations for orphan drugs in EU
was recognition of an emotion that patients suffering from rare
conditions should be entitled to the same quality of treatment as
other patients. This was recognized and protected in European law
with the European regulation 141/2000. Profitable incentives were
given in 141/2000 regulation to try to motivate the manufacturers
and researchers to develop the orphan medicinal products.

12. The regulation (EC) No. 141/2000 for orphan drugs was approved
on 16 December 1999 by the European Parliament and the
Council. The aim was to construct a Committee on Orphan
Medicinal Products (COMP) as a subunit of the European
Medicines Evaluation Agency (EMEA) which would boost the
biotechnological and pharmaceutical industry to discover,
develop and market orphan drugs.
The COMP consists of 28 members nominated by each the
European Member State; three members are nominated by the
European Commission and three agents of patient associations.
The Committee of Propriety Medicinal Products remains in
contact with COMP for scientific evaluation of medicinal products
and both are accountable for EMEA. The participation of patient
association’s agents of COMP has been very considerable in the
process of emerging new treatments for rare diseases in Europe.

13. ORPHAN DESIGNATION
 “The orphan drug act(ODA) provides for granting special
status to a drug or biological product to treat a rare
disease or condition upon request of a sponsor.This status
is referred to as ORPHAN DESIGNATION or sometimes
orphan status.”
ORPHAN DRUG DESIGNATION IN US
 The Orphan Drug Designation program provides orphan
status to drugs and biologics which are defined as those
intended for the safe and effective treatment, diagnosis
or prevention of rare diseases/disorders that affect fewer
than 200,000 people in the U.S., or that affect more than
200,000 persons but are not expected to recover the costs
of developing and marketing a treatment drug.

14. The OOPD(office of orphan product development) is answerable
for assessing, awarding, and watching the progress of orphan drug
grants. The ODA make available for granting special status, orphan
drug designation, of a product to treat a rare disease or condition
upon request of a sponsor.
Orphan Drug Status
This may be entitled to a drug if it meets the following criteria:
• A drug is not approved earlier
• An approved drug with new orphan indication
• A drug proved clinically superiority over previously approved drug
of same category.

15. ORPHAN DRUG DESIGNATION IN THE EUROPE
Orphan designation in Europe is based on the criteria laid down in
Regulation (EC) No 141/2000. Designation is free of charge, and may
be obtained at any stage of development before an application for
marketing authorization is made, provided proper scientific justification
of the intended use is submitted.
EMA's role in orphan designation
The Agency is responsible for reviewing applications from sponsors
for orphan designation.To qualify for orphan designation, a medicine
must meet a number of criteria:
•the prevalence of the condition in the EU must not be more than 5 in
10,000 or it must be unlikely that marketing of the medicine would
generate sufficient returns to justify the investment needed for its
development;

16. •no satisfactory method of diagnosis, prevention or treatment of the
condition concerned can be authorized or if such a method exists, the
medicine must be of significant benefit to those affected by the
condition.
Applications for orphan designation are examined by the
EMA's Committee for Orphan Medicinal Products (COMP), using the
network of experts that the Committee has built up. The evaluation
process takes a maximum of 90 days from validation.
•it must be intended for the treatment, prevention or diagnosis of a
disease that is life-threatening or chronically debilitating;

17. MARKET EXCLUSIVITY OF ORPHAN DRUGS
Marketing Exclusivity is exclusive marketing rights granted by the
FDA upon approval of a drug and can run concurrently.
ORPHAN DRUG EXCLUSIVITY IN US
•The Orphan Drug Act provides drug manufacturers with ‘7’ years of
market exclusivity period after FDA’s approval of the drug, as well as
research grants and tax credits for each new orphan drug developed.
•If a product is granted orphan drug exclusivity, FDA may not
approve (but may accept) applications for generic or second
innovator products that contain the same active ingredient and are
labeled for the same orphan indication. However, FDA may accept
and approve applications for drugs having the same active moiety,
for a different indication.

18. ORPHAN DRUG EXCLUSIVITY IN EUROPE
The benefits of orphan drug designation in the EU are vast. If
marketing authorization is granted pursuant to the EU’s centralized
procedure or by all Member States, the Community and the Member
States may not accept or grant for ‘10’ years, a new marketing
authorization or accept an application to extend an existing marketing
authorization, for the same therapeutic indication as an orphan drug.
Although market exclusivity for orphan drugs is generally granted
for a period of 10 years, it may be extended to 12 years for pediatric
products, or may be reduced to six years if, at the end of the fifth
year of exclusivity, the drug no longer satisfies the original
designation criteria.

19. INCENTIVES FOR ORPHAN DRUG LEGISLATION IN US
AND EUROPE
The Orphan Drug Act (1983) established
several incentives to encourage the
development of orphan drugs (ODs) to treat
rare diseases and conditions. This study
analyzed the characteristics of OD
designations, approvals, sponsors, and
evaluated the effective patent and market
exclusivity life of orphan new molecular
entities (NMEs) approved in the US
between 1983 and 2007.

20. Incentives Of ODA

21. INCENTIVES FOR ORPHAN DRUG IN EUROPE
• Market exclusivity
For 10 years after the granting of a marketing authorization (approval for
sale), orphan medicinal products benefit from market exclusivity in the
EU. During that period, directly competitive similar products cannot
normally be placed on the market.
• Protocol assistance
The Agency can provide scientific advice to optimize development and
guidance on preparing a dossier that will meet European regulatory
requirements.
• Fee reductions
A special fund from the European Commission, agreed annually by the
European Parliament, is used by the Agency to grant fee reductions.
• EU-funded research
Sponsors developing orphan medicinal products may be eligible for
grants from EU and Member State programmes and initiatives
supporting research and development, including the Commission's
framework programme.

22. ALONE WE ARE
“ RARE”
TOGETHER WE ARE
“STRONG”
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