Orphan Diseases - An Indian Perspective

K. Mangathayaru, A. Sivakumar, K. Chitra, K.Sujatha, K. Sravan            

K. Mangathayaru     

Orphan Diseases

Diseases which manifest in
patient populations representing at the maximum 6-8% of the world population
are defined as rare diseases.

¹
They are pathologies whose incidence
at birth is less than 1 in 2000. 50% of these appear when the sufferer has
reached adult age. Today there are over 
5000  rare diseases listed  in 
the  world  with five 
new  rare  diseases 
being  described  every week in  the 
medical  literature. 2    

The high cost of drug
development, coupled with the low return on investment, discourage the
pharmaceutical industry from developing products for extremely small patient
populations.  Rare  diseases 
thus  'Orphaned'  by 
the  pharmaceutical industry  and 
having  few  approved 
drug  Treatment options available
are called ‘Orphan diseases’.

Orphan Drug Act (ODA)

The need to
develop products to target these orphan diseases was first keenly felt in the
United  States where rare  diseases 
support  groups  representing 
the fewer  than 200,000  rare 
disease  sufferers  in 
this  country  worked 
aggressively  to  raise 
public awareness  and  to 
promote  legislation  to 
encourage  the  development 
of  such  drugs for 
saving  the  lives 
of  these  patients. 
As a result the Orphan Drug Act’ was passed by the US Congress in 1982
and signed into a law  in  January 
1983. The objectives of this legislation was to stimulate the
development of drugs and biological products for  the 
treatment  of  rare 
diseases  collectively  affecting 
25 million  Americans. The  ODA 
administered  through  the 
US  FDA  office 
of  orphan  product development  offers 
incentives  for  pharmaceutical  and 
biotechnology companies  to  develop 
drugs  for  rare  disorders.
³
  The
incentives include new drug applications fee waiver, tax credits for
clinical  research on  orphan products, grant funding for the investigation  of rare 
disease  treatment  and 
market  exclusivity.  Market 
exclusivity  is  the 
most  powerful  incentive.
⁴
  It 
assures  that  no 
other  sponsor  will receive 
FDA  marketing  approval 
for  the  same 
drug   for  the 
same  indication  for 
7  years  after 
marketing  approval  of 
the  innovators  product. Also 
it  is  a  more  comprehensive 
incentive  than  a 
patent  because  product approval  and 
orphan  designation  by 
the  FDA  are 
essentially  the  only 
requirements  for  orphan  market  exclusivity. 
Patent requirements  on  the  other  hand 
are  stringent  and 
require  that  drugs 
are  novel  and 
their  production non-obvious. ⁵ 
          

Thus  drugs 
ordinarily  ineligible  for 
patent  protection  such 
as  albuterol,  clonidine 
or  caffeine might  be 
eligible  for  Orphan  exclusivity. 
Also, unlike  patents,  Orphan 
market  exclusivity  becomes 
effective  on   the date 
of  the  FDA 
marketing  approval  and 
therefore  no  time 
is  expended  during 
product  development.
⁶

Impact
of The Act

Since  the 
introduction  of  ODA, 
nearly  1100  drugs 
and  biological products  have been 
designated  as  Orphan 
products . The  FDA  has approved 
231  of  these 
for  marketing,  thereby 
facilitating  treatment  for an 
estimated  11  million 
patients  in  the  USA.
⁷
  Also 
the  FDA  has so 
far  offered  370 
extra  mural  clinical  
grants  totaling  more 
than  $150  million 
for  orphan  product  developers.
⁸
 Approximately 
85%  of Orphan  designations 
in  USA  are 
being  used  for 
the  treatment  of  serious  life 
threatening  diseases.

The
highest  percentage (31%)  is 
for  rare  forms 
of  cancer,  such 
as  ovarian  cancer 
or  hairy cell leukemia. Metabolic
disorders represent the second largest group of orphan designations (11%).
⁹
Approximately 20% of the orphan designations are for novel biotechnology
products, such as therapeutic and diagnostic monoclonal antibodies, therapeutic
enzymes, novel drug delivery biomolecules, tissue engineered products,
combinations of cells, tissues and other bioactive materials used as tissue
regenerators. Orphan drugs and biological products are thus diverse and include
older drugs with new uses, new molecular (NME`s) and recombinant DNA products,
Some drugs developed for a larger disease group having a low risk reward ratio,
may end up being used for a more severe rare disease despite the adverse
effects. Thalidomide is a classical example of a formerly banned
drug being reintroduced for an orphan indication (multiple myeloma).

The ODA has
also been a great booster to the biotech industry. Many rare diseases are
ideally suited for treatment with biotech products. Serious or life threatening
hereditary disorders such as enzyme deficiencies stemming from a rare single
gene defect are potentially treatable with recombinantly produced replacement
proteins introduced for the first time in 1970`s. These molecules that are too
difficult and expensive for manufacture by conventional pharmaceutical
companies began to be developed by small biotech companies once the act went into
effect. Thus the ODA legislation in 1983 coincided with the founding of several
biotech companies that stimulated by the incentives of the ODA focused on
the rare disease market. A recent study by the Tuft’s center for the study of
drug development found that from 1983-92 the biotech industry secured 19% of
all orphan drug approvals and by 2001 it has grown to 41%.

In the 1

^st
decades
of its introduction, this act stirred up a controversy.  In 1989 Amgen, then a small biotech company
sought FDA approval under the ODA to market epoetin Alfa (Epogen), for anaemia
in end-stage kidney failure - a rare indication. However once on the market
this drug proved useful for other more common indications like restoration of
RBC`s in bone marrow suppression following cancer chemotherapy, or AIDS
therapy, and also it reduced the need for transfusions in surgery patients .It
was prescribed by all and the new drug started making profit in billions.
Genentech`s human growth hormone (HGH) and Glaxosmith Kline’s AZT followed the
same pattern with HGH being generally prescribed for short statured 
children and AZT for AIDS which soon became a pandemic. Questions began to be
asked about prevention of abuse of ODA as of the 10 best selling biotech
drugs world wide in 2001, five were originally approved for orphan indications
in addition to their original use. This afforded their developers seven years
of market exclusivity and thus great sales! Indeed the biggest money
making orphan products helped to launch some of the major players in the
biotech industry including Amgen and Genentech.

Rare
diseases and Orphan drugs have been boons to applied pharmaceutical research.

¹⁰
.
A striking example of an orphan drug technology that blossomed into widespread
use is Pegylation, the process of adding a waxy substance called
polyethylene glycol (PEG), which slows the drug’s clearance from the blood
stream and masks it from attack by the immune system. Pegylation was debuted in
1990 in Enzon`s orphan drug Adagen for the treatment of ADA-SCID. Although only
a few dozen children worldwide suffer from this condition, pegylation
technology is now used in PEG-Intron, part of a combination treatment for
hepatitis C, and has tremendous potential in other therapeutic applications.

Rare Diseases In Future

With the
successful completion of the human genome project, Pharmacogenomics is likely
to make an increasingly important contribution to pharmacotherapy.

¹¹

Using genotypic markers disease subsets will be identified within a homogenous
disease population. So what is now thought of and treated as a homogenous
disease might actually be an aggregate of genotypes each with varied responses
to a particular drug therapy. This will favor drug design and development to
target specific genotypes, thus personalizing medicine. A possible outcome is,
more orphan diseases will be identified, and thus newer drugs will be needed.
This will be a challenge to the Biotechnology industry and also to the Pharmaceutical
industry which has hitherto relied on mass sales of identical drugs to large,
poorly differentiated patient populations.

Global Scenario
  

The ODA which marked its 20th Anniversary in 2003 is
considered one of the most successful health care laws that have been passed in
recent history. It has had a beneficial impact on the public health by
providing incentives to develop new products for rare diseases. Since the act’s
introduction in the
US

229 orphan drugs that together treat 11 million rare
disease sufferers have entered the market. Existing Pharmaceutical and biotech
companies have been induced to develop orphan products and new companies have
been founded for the purpose of addressing unmet needs.

The success of
the ODA has awakened global awareness and prompted the introduction of similar
legislation in other countries.

Japan
has passed Orphan Drug Law in 1993 and the European Union has had its own
legislation in 1999.Australia follows the US Act recognizing orphan drugs
approved in the
US

for the same indication, when the prevalence of the disease in the Australian
population is not more than 1 person per 500.

Singapore

has its own Orphan Drug
Exemption Act 1991. Other countries that are seeking to establish similar
legislations include

South Korea

,

Canada

and

New Zealand

. 

India & Orphan Drugs:

The need for
such an act is thus evident and it need from initiative from the Indian
Pharmacists and the Government to implement such Laws which would strengthen
the health infrastructure and provide relief to the numerous rare disease sufferers
throughout the country. In our country, a group of pharmacologists at a
conference held by the Indian Drugs Manufactures Association in 2001, requested
the Indian Government to institute the Orphan Drug Act in India.

¹²

If
such legislation could be implemented, it will be a boon not only to our Pharmaceutical
and Biotechnological Industry but will also bring relief to the unlisted very
possibly large groups of rare disease sufferers, in our country.

References

1.
Spiker,
B., In; Schelnberg, Hand Walshe, J.M, Eds, Orphan diseases and  Orphan drugs, Manchester University Press,
Manchester,1986,112.

2.
www.rarediseases.org/info/about.html.

3.

www.fda.gov/orphan/oda.htm.

4.

Rohde,
D.D: The Orphan Drug Act: an engine of innovation, at what cost?  Food Drug Law J., 2000, 55, 125-143.

5.

Title
35,

United States
Code (USC) Sections 102-103.

6.

Mathiew,
M, In; New Drug Developments: A Regulatory Overview 4th Edn, Paraxel
International,

Massachusetts
,
1997.

7.

www.fda.gov/orphan/designat/list.htm.

8.

Maeder,
T. The Orphan Drug Backlash, Scientific American, 2003, 288, 83.

9.

Haffner

,

M.E.
, Whitley, J.  and Moses, M. Two decades of orphan drug development, Nature Review:
Drug Discovery, 2002, 1, 821-825.

10.

Maeder,
T. The Orphan Drug Backlash, Scientific American, 2003, 283, 85.

11.

Golden
JB; Curr Opin. Drug Disc. Dev 2003, 6, 310-16.

12.

Rinat
Ariely, In; The Rise of Biopharmaceutical Orphan Drug Adoption, Frost and
Sullivan, (2001).

Table.1 Rare
diseases and Orphan drugs.