rare diseases drug development

1. 1
DEPARTMENT OF PHARMACEUTICAL
QUALITY ASSURANCE
PQA-MQA106S
Seminar Topic:
‘‘ORPHAN DRUG DESIGNATIONS AND
APPROVALS’’
Submitted by:
Supraja kotam
230609019
Department of Pharmaceutical Quality Assurance
Semester I
Under the Guidance of:
Dr. Sudheer Moorkoth
Professor & Head of the Department
Department of Pharmaceutical Quality Assurance, MCOPS

2. 2
TABLE OF CONTENTS
S.N0 TOPIC PAGE NUMBER
1
Introduction
3 -5
2 incentives 6-7
3 designation 8-14
4 regulation 15-20
5 Indian Scenario 21-24
6
Challenges for development
25-28
7 Approvals 29-31
8 References 32-33

3. 3
1. INTRODUCTION
Rare diseases
A rare disease is a disease that affects a small percentage of the population. In
general, an orphan disease is a rare disease whose rarity means there is a lack of a
market large enough to gain support and resources for discovering treatments for it,
except by the government granting economically advantageous conditions to
creating and selling such treatments7
.
Definition of rare changes Some rely solely on the number of people living with a
disease, and other definitions include other factors, such as the existence of
adequate treatments or the severity of the disease.
In United States, the Rare Diseases Act of 2002 defines rare disease strictly
according to prevalence, specifically "any disease or condition that affects fewer
than 200,000 people in the United States".
In Japan, the legal definition of a rare disease is one that affects fewer than 50,000
patients in Japan, or about 1 in 2,500 people8
.
What are orphan drugs ?
Orphan drugs are medicinal products intended for diagnosis, prevention or
treatment of life-threatening or very serious diseases or disorders that are rare.
These drugs are highly innovative and provided with substantial gains in reducing
unmet medical needs for patients with orphan diseases1
.
As the number of persons suffering from individual rare diseases is small, they do
not constitute a significant market for drug manufacturers to develop and bring into

4. 4
market. For this reason, rare diseases are also called ‘orphan diseases’ and drugs to
treat them are called “orphan drugs”.
Orphan drugs address public health needs but may not be developed by
pharmaceutical companies for economic reasons and an orphan drug would not be
profitable to produce without government assistance, due to the less population of
patients affected by the conditions. Here the term “drug” will refer to both drugs
and biologic products1
ORPHAN DRUG ACT (1983)
The Food and Drug Administration (FDA) created the Orphan Drug Act to
encourage and provide special incentives to drug companies that undertake the
development of orphan drugs.
In USA, the Orphan Drug Act was passed in 1983 to give drug companies
incentives and develop treatments for rare diseases that target diseases affecting
fewer than 200,000 people.
several countries have through legislation like Orphan Drug Act (ODA), provided
incentives to drug manufactures to encourage them to manufacture drugs for rare
diseases and motivate drug companies to develop orphan products.
In the US alone over 2,000 molecules have received orphan drug designation and
the FDA has approved more than 350 orphan drugs since the ODA went into effect
.
IMPLEMENTATION AND IMPACT
The Orphan Drug Act - Implementation and Impact advocates report that orphan
products became accessible to patients although they can be costly and in limited
supply.

5. 5
Insurance typically pays for the treatments, and companies offer patient assistance
programs to help patients obtain their products.
Fig;no 1. impact of orphan drug on availability of various therapies
From the last few years have seen rapid influx in approval of orphan drugs which
is mainly attributed to the restless efforts by scientists and rising awareness among
population. Several orphan drugs including Imbruvica, Trikafta, Hemlibra, and
others have shown robust response in the market.
some of the major drugs that are used in the treatment of orphan diseases are:
o Alexion- Originally developed for the blood disorder paroxysmal nocturnal
hemoglobinuria, but now used as treatment for atypical hemolytic uremic
syndrome.
o Revlimid- Originally developed for blood cancer (myeloma), but now used
for late-stage non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia.

6. 6
o Kogenate is used to treat or prevent bleeding episodes in adults and children
with haemophilia A.
o Vaccinia Immune Globulin IV- It is a first-line drug treatment for serious
smallpox vaccination complications.
o Kalydeco- It is used to treat cystic fibrosis (It is a rare genetic disorder that
primarily affects the lungs but can also affect the pancreas, liver, intestine,
kidneys, and liver).
o alexion and Revlimid Originally developed for blood disorder paroxysmal
nocturnal hemoglobinuria and myeloma, but now used in treatment for
atypical hemolytic uremic syndrome and chronic lymphocytic leukemia
respectively.
2. ORPHAN DRUG INCENTIVES
These incentives have encouraged industry interest and accelerated research on
rare diseases, allowing patients with orphan diseases access to treatments.
o Federal funding allocation: Pharmaceutical companies receive grants and
contracts from the government to support the clinical trials of orphan drugs
and products.
o Tax credit: Manufacturers are eligible for a tax credit that covers 50% of the
costs associated with clinical testing. These tax credits are administered by
the Internal Revenue Service or IRS and not by the FDA

7. 7
o Exclusive marketing rights: Pharma companies are granted exclusive
marketing rights for the orphan drug for 7 to 10 years from the date of
marketing approval including protection from imports. (CFR Title 21 Part
316)
o Synchronization : The act grants the FDA authority in coordinating orphan
drug development, reviewing drug status requests approving and granting
privileges to pharmaceutical companies. The Office of Orphan Product
Development (OOPD) is also established to facilitate regulatory work within
the FDA.
o Fee Exemption : Sponsors eligible to receive a waiver of the Prescription
Drug User application fee that is collected when a marketing application is
submitted. The typical application fee is currently over $2 million dollars.
o Reduction in revenue dropping : Orphan drugs may help pharma
companies to decrease the impact of income losses caused by patent
expiries of blockbuster drugs. The new business model of orphan drugs
could offer an integrated healthcare solution that enables pharma companies
to develop newer areas of therapeutics, diagnosis, treatment, monitoring, and
patient support.
o Other Profits : In addition to exclusive rights and cost benefits, the FDA
will provide protocol assistance, potential decreased wait-time for drug
approval, discounts on registration fees.
o Ability to qualify to compete for research grants from the Office of Orphan
Products Development (OOPD) to support clinical studies for orphan drugs
This designation is not intended for drug companies to recover all the costs of drug
development, but rather as a cost reduction and regulatory streamlining mechanism

8. 8
to encourage and provide special assistance to companies that develop drugs for
rare patient populations.
However, extended market exclusivity has been associated with unacceptably
high drug costs; both for newly developed drugs and even for drugs which were
previously widely available. 4
orphan incentive programs administered by the US (FDA):
 The Orphan Drug Designation Program
 The Humanitarian Use Device (HUD) Designation Program,
 The Orphan Products Clinical Trials Grants Program,
 The Pediatric Device Consortia (PDC) Grant Program,
 The Orphan Products Natural History Grants Program
3. ORPHAN DRUG DESIGNATION
The FDA’s Office of Orphan Products Development (OOPD) is responsible for
reviewing applications for orphan drug designation. The OOPD has recently
adjusted its review timeline target from within 90 days of receipt to within 120
days of receipt. FDA's act of granting a request for designation is under section
526 of the O.D act.
Sponsor

9. 9
The entity that assumes responsibility for a clinical or nonclinical investigation of a
drug, including the responsibility for compliance with applicable provisions of the
act and regulations.
A sponsor may be an individual, partnership, corporation, or Government agency
and may be a manufacturer, scientific institution, or an investigator regularly and
lawfully engaged in the investigation of drugs. For purposes of the Orphan Drug
Act, FDA considers the real party or parties in interest to be a sponsor.
Orphan Drug Designation Application
Requests for an orphan drug designation can be submitted through the FDA Form
4035. The FDA will complete a review of the orphan drug designation request
within 120 days of its receipt. The components required for submission of Form
4035 include:
 Information about the sponsor and drug product
 A description of the rare disease or condition of interest along with reasons
why such therapy is needed
 Scientific rationale for the use of the drug for the rare disease or condition
 A summary of the regulatory status and marketing history of the drug in the
United States and in other countries
 Documentation to demonstrate that the disease or condition meets
qualifications to be a rare disease.
A sponsor may request orphan-drug designation of a previously unapproved drug,
or of a new use for an already marketed drug.

10. 10
More than one sponsor may receive orphan-drug designation of the same drug for
the same rare disease or condition, but each sponsor seeking orphan-drug
designation must file a complete request for designation.
 Content and format of request for O.D designation
A sponsor shall submit two copies of a completed, dated, and signed request for
designation that contains the following:
(1) A statement that the sponsor requests orphan-drug designation for a rare
disease or condition, which shall be identified with specificity.
(2) The name and address of the sponsor; the name of the sponsor's primary
contact person and/or resident agent including title, address, telephone number,
and email address; the generic and trade name, if any, of the drug, or, if neither
is available, the chemical name or a meaningful descriptive name of the drug;
and the name and address of the source of the drug if it is not manufactured by
the sponsor.
(3) A description of the rare disease or condition for which the drug is being or
will be investigated, the proposed use of the drug, and the reasons why such
therapy is needed
.(4) A description of the drug, to include the identity of
The active moiety - if it is a drug composed of small molecules.
The principal molecular structural features - if it is composed of macro
molecules.

11. 11
The physical and chemical properties - if these characteristics can be
determined; and a discussion of the scientific rationale.
(5) A summary of the regulatory status and marketing history of the drug in the
United States and in foreign countries .
(6) Animal toxicology studies are generally not relevant to a request for orphan-
drug designation. Copies of pertinent unpublished and published papers are also
required.
(7) All relevant data from in vitro laboratory studies, preclinical efficacy studies
conducted in an animal model for the human disease or condition, and clinical
experience with the drug in the rare disease or condition that are available to the
sponsor, whether positive, negative, or inconclusive.
(8) Documentation, with appended authoritative references, to demonstrate all the
requirements.
 Considerations and Requirements
When reviewing a request for orphan drug designation, FDA keeps in a view that
the mechanism of action of the drug to determine what distinct disease or condition
the drug is intended to treat, diagnose or prevent.
Whether a given medical condition constitutes a distinct disease or condition for
the purpose of orphan-drug designation depends on a number of factors, assessed
cumulatively, including:
 Pathogenesis of the disease or condition
 prognosis of the disease or condition
 resistance to treatment

12. 12
These factors are analyzed in the context of the specific drug for which
designation is requested
Fig.no 2 . No of orphan drug product approved by every year
 The declination and dismiss
FDA will refuse to grant a request for orphan-drug designation if any of the
following reasons apply:
The drug is not intended for a rare disease or condition because:

13. 13
(1) There is insufficient evidence to support the estimate that the drug is
intended for treatment of a disease/condition prevention or diagnosis in fewer
than 200,000 people in the United States.
(2) There is insufficient information about the drug, or the disease or condition
for which it is intended, to establish a medically plausible basis for expecting
the drug to be effective in the prevention, diagnosis, or treatment of that disease
or condition.
(3) The drug is otherwise the same drug as an already approved drug for the
same rare disease or condition and the sponsor has not submitted a medically
plausible hypothesis for the possible clinical superiority of the subsequent drug.
IMPRORTANCE
o These drugs can help alleviate the revenue loss when blockbuster drug
patents expire.
o Academic physician-scientists have taken the initiative to develop orphan
drugs to make them more affordable and effective, and they have
successfully treated rare diseases.
o Sometimes, a drug may be considered an "orphan" because it is initially
developed for a common condition but proves challenging to develop for
another rare indication.
Orphan Drug Product Designation and Grant Programs
The clinical trial grants program - provides funds to help offset the costs of
clinical trials that will test the safety and efficacy of products intended to treat a
rare disease. At any one time, there are typically 60 to 85 ongoing funded projects
under this grant program.

14. 14
The natural history grants program - funds well-designed, protocol-driven
natural history studies that address knowledge gaps, support clinical trials, and
advance rare disease medical product development. The FDA defines a natural
history study as one that “describes the course of a disease over time, identifying
demographic, genetic, environmental, and other variables that correlate with its
development and outcomes.”
In 2022, several drugs received orphan drug designation from the FDA.
Here are some examples:
1. BB-Vec: Intended to treat Epidermolysis bullosa. The Biologics License
Application (BLA) was accepted on February 17, 2023
2. Omaveloxolone: Intended to treat Friedreich’s ataxia. The New Drug
Application (NDA) was accepted on February 28, 2023
3. Trofinetide: Intended to treat Rett syndrome. The NDA was accepted on
March 23, 2023
4. SRP-9001 (delandistrogene moxeparvovec): Intended to treat Duchenne
muscular dystrophy. The BLA was accepted on May 29, 2023

15. 15
.
Fig.no 3 orphan designation process
4. Why orphan drug regulation is needed?
1. Limited safety and efficacy data: Orphan drugs are typically developed for
rare diseases or conditions that affect a small patient population. Without

16. 16
regulatory oversight, there may be limited data on their safety and efficacy,
potentially putting patients at risk.
2. Inconsistent quality: Regulation helps ensure that orphan drugs meet certain
quality standards. Without regulation, there is a risk of inconsistency in drug
quality, which can affect patient outcomes.
3. Lack of incentives for development: Regulatory incentives, such as extended
market exclusivity and tax incentives, encourage pharmaceutical companies to
invest in the development of orphan drugs. Without these incentives, there may be
reduced motivation to develop treatments for rare diseases.
4. High costs: Regulatory oversight can help ensure that orphan drugs are priced
reasonably. Without regulation, there may be a lack of price control, leading to
excessively high costs for these medications, which can burden patients and
healthcare systems.
5. Limited access: Regulatory agencies play a role in assessing the need for
orphan drugs and approving them for the market. Without regulation, there may be
limitations on access to these drugs, leaving patients with rare diseases with fewer
treatment options.
In general the regulation of orphan drugs is essential to protect patient safety,
ensure drug quality, provide incentives for development, control costs, and expand
access to treatments for rare diseases.
Example 1
On March 23, 2020, the FDA granted orphan drug status to Gilead Sciences for the
antiviral drug ‘Remdesivir’ (originally developed to treat Ebola), which was then
tested for COVID-19.

17. 17
However, on March 25, Gilead announced that it submitted a request to the FDA to
remove its orphan drug designation for remdesivir, and the FDA subsequently
removed the drug from its orphan drug list.
Previously, Gilead had repeatedly urged the FDA to grant orphan status to the drug
remdesivir to expedite drug approval.
Similarly in recent years many drug companies have been accused of profiting
from sales by taking advantage of the law.
Example 2
Imatinib mesylate, is a blockbuster oral-dose drug approved to treat nine
different cancers, granted orphan drug exclusivity 4 times since 2001.
It also got approved for multiple indications and are not used solely to treat rare
diseases. Many of these drugs are billion dollar blockbusters and are targeted by
generics.
It shows the financial interest of pharmaceutical companies to focus and efforts on
drugs targeting common diseases to maximize the potential patient base and thus
the potential to recoup drug development costs and generate profits.
Example 3
Generic companies take a much smaller gamble than the manufacturers of the
pioneer product because they know the approval fate of the drug prior to investing
development dollars and they don't need to deal with the large cost, complications
associated with finding patient populations on whom to run efficacy trials.
High priced innovator drugs and limited market competition allowing generic
companies to demand relatively high prices for orphan drug copycats.

18. 18
Innovator companies often release an orphan drug only in select countries; this
opens the opportunity for generic manufacturers to target larger, global patient
populations and perhaps control some smaller markets.
How prices are regulated?
Orphan Drugs, as identified by the Health Ministry from to time, are exempt from
price regulation. India does not follow a system requiring a reference price based
on a basket of countries.
Can Orphan Drugs be reimbursed?
The Union Health Ministry as well as the various state health ministries have set
up technical committees known as the Central Technical Committee (“CTC”) and
the State Technical Committee (“STC”) respectively, to review applications by
patients requesting financial assistance for treatment of rare diseases.
The NPTRD (National Policy for Treatment of Rare Diseases ) has also proposed a
financial assistance scheme for treatment of rare diseases. The scheme divides rare
diseases into three categories and provides financial assistance.
significant legal/judicial developments in relation to Orphan Drugs in
country :
The constitutional obligation of the state to ensure access to life saving drugs has
been formally recognized by the Delhi High Court in (“Mohd. Ahmed Case”).
Delhi High Court directed the Government to provide the minor patient with
enzyme replacement therapy worth INR 600,000 (USD 8,334) per month as a
treatment to gaucher. He was offered financial assistance with respect to the
treatment of the rare disease.

19. 19
Regulation of orphan drugs is crucial to ensure that patients with rare diseases have
access to safe and effective treatments. Without regulation, the development of
drugs for rare diseases would be less incentivized, as the market for these drugs is
relatively small.6
If there were no regulation for orphan drugs, it would be difficult to ensure that
these drugs are safe and effective. The development of drugs would be less and
patients with rare diseases would have fewer treatment options. It is important to
continue to support the development of drugs for rare diseases through regulation
(*) Abbreviations :
FDA: Food and Drug Administration
OOPD: Office of Orphan Products and Development
MHLW: Ministry of Health, Labour and Welfare
TGA: Therapeutic Good Administration
EMEA: European Agency for the Evaluation of Medicinal Products
COMP: Committee for Orphan Medicinal Products
NIH: National Health Institute

20. 20
comparison of the various policies on orphan drugs worldwide
USA Japan Australia EU
Legal framework
Orphan Drug Act
(1983)
Orphan Drug
Regulation (1993)
Orphan Drug
Policy
(1998)
Regulation (CE)
N°141/2000 (2000)
Administrative authorities
involved
FDA / OOPD (*)
MHLW/OPSR (*)
(Orphan Drug
Division)
TGA (*) EMEA / COMP (*)
Estimation of the population
affected, prevalence rate
(per 10,000 individuals)
20 millions
7,3
No information
No
information
25-30 millions
6, 6-8
Marketing exclusivity 7 years 10 years
5 years
(similar to
other drugs)
10 years
Tax credit
yes : 50% for
clinical studies
yes : 6% for any
type of study +
limited to 10% of
the company's
corporation tax
no
managed by the
member states
Grants for research
programs
of NIH and others
governmental funds no
'FP6' + national
measures
Reconsideration of
applications for orphan
designation
No yes
yes
(every 12
months)
yes (every 6 years)
Technical assistance for
elaboration of the
application file
yes yes no yes
Accelerated marketing
procedure
yes yes yes
yes (via the
centralised
procedure)

21. 21
5. ORPHAN DRUGS IN INDIA
India does not have laws on orphan drugs though CDSCO defined orphan drugs as
those intended to treat a condition which affects fewer than 200,000 people.
Time to time scientific and patient communities expressed the needs for
government initiatives toward rare disease. The first attempt to bring together all
experts of rare disease under a common platform was initiated by INSA( Indian
national science academy) which conducted the first of the kind rare disease
workshop entitled “To Develop a Scientific Program for Research on Rare
Diseases” in 2016.
o In 2019 – India’s Central Drugs Standard Control Organization (CDSCO)
implemented its new Drugs and Clinical Trials Rules.
o The new rules define orphan drugs – for the first time – as drugs to treat
conditions affecting less than 500,000 people in India.
o As per the new rules, Indian regulators have now been empowered to
exempt orphan drugs from Phase III and IV clinical trials.
o By selling only to a small group of patients, a drug manufacturer will likely
not be able to recover the development and marketing costs, so the
Government of India has implemented a new ‘National Policy for Rare
Diseases (NPRD)’ in the year 2021 to encourage the production of these
Orphan drugs.
o On 13 January 2021, the Government of India introduced a Comprehensive
‘National Policy For Rare Diseases 2021’ (In which included – Research &
development to manufacture orphan drugs, treatment of rare diseases, etc.)
replacing its ‘National Policy for Treatment of Rare Diseases 2017’

22. 22
The Government of India has introduced a new drug policy to strengthen
government and private institutions for the development of orphan medicine in the
year 2021 to assess the spectrum and burden of orphan diseases and for public
awareness programs about orphan diseases.
National Policy for Rare Diseases (NPRD) 2021
The central government laid out the National Policy for Treatment of Rare
Diseases in 2017. But the government put the policy on hold, citing
implementation challenges.
As per the states, some issues with the policy regarding -
cost-sharing, disease coverage, and patient eligibility for rare disease treatment
under this policy were a need for more clarity. To address these questions, a review
committee was constituted in 2018, which submitted its recommendations on 13
January 2021.
The National Policy for Rare Diseases (NPRD) 2021 has the following objectives:
o The National Policy on Rare Diseases (NPRD), 2021, includes provisions
for the promotion of research and development for diagnosing and treating rare
diseases.
o Improving the public health system to examine and detect rare diseases early
to prevent and treat them.
o Making a conducive environment for the indigenous production of drugs for
rare diseases at affordable prices.
o Improving India’s tertiary health care sectors and providing better diagnostic
and treatment options.

23. 23
In addition, issues such as a greater emphasis on R&D and local production of
orphan drugs have been included.
Cdsco Initiative
By a circular dated July 3, 2014, the CDSCO issued a notice regarding waiver of
clinical trial for approval of new drug in the Indian population, for drugs which are
already approved outside India, and it was mentioned that this waiver can only be
possible in case of orphan drugs for rare disease and drugs indicated for diseases
and condition where there is no therapy.
In another meeting at a later date between pharma stakeholders and DCG(I), held
on May 4, 2016, on exploring of possibilities to provide cheaper medicines for
patients with rare diseases.
IDMA and OPPI ( organization of pharmaceutical producers India) were given the
responsibility to formulate the Indian definition of rare disease, given the
responsibility to revise timelines for orphan drug approvals, and a separate cell was
suggested to address the issues of rare diseases, possibility of separate pricing
mechanism for orphan drugs, and possibility of custom duty exemption.
ICMR initiative
ICMR are inviting projects for orphan disease research and initiation of registry
for rare disease and sponsoring/organizing workshops/conferences/training
programs on rare disease.

24. 24
The National Initiative for Rare Diseases (NIRD) was organized jointly by ICMR,
AIIMS, JNU, PRESIDE and It was decided that first step is to identify patients
with rare disease.
“Indian rare disease registry” was launched on April 27, 2017. This registry
covered all rare and ultra rare diseases prevalent in India. The registry is first
intended to be hospital based and later population based. The objectives are
identification of the rare disease patients; use that data for policy framing and to
guide future research. Other major benefits are that monitoring prevalence,
incidence, and natural history of disease will become easy with regard to the Indian
context.
Pharmaceutical export promotion council initiative
Pharmaceutical export promotion council, Ministry of commerce and industry,
India, conducts regular seminars, awareness campaigns regarding quality
compliance and orphan drugs, quality culture in good manufacturing practice
(GMP) compliance overseas marketing strategies, opportunities for orphan drugs,
IPR and interaction with Food and Drug Administration (FDA) of other countries,
etc., and takes care of orphan drug export and other related strategy such as GMP
compliance, awareness, and strategy maker in collaboration with FDA of other
countries
Nongovernmental organization initiative
Organization for Rare Diseases India (ORDI) is a nonprofit-based voluntarily
organization which was established to deal with the rare disease condition in the
Indian population. The ORDI team members belong to different disciplines that are

25. 25
science and nonscience background. ORDI deals with the matters related to the
rare disease ssuch as unique challenges in dealing with rare disease.
CSIR and IGIB initiative
IGIB, New Delhi, has conducted project funded by CSIR, named as “Genomics for
Understanding Rare Diseases India Alliance Network (Guardian),” for the purpose
to bring together and understand novel genetic variations to achieve translational
applications by both clinicians and basic science researchers.
Uttar Pradesh Government initiative
Incidence of hemophilia in India is estimated to be 1 in 5,000. for treatment
purpose, clotting factors used are very costly. In the year 2010, the Uttar Pradesh
Government took an initiative to cover the cost of clotting factors.
6. Challenges faced for progress in O.D
Developing treatments for rare diseases has many challenges. These challenges are
different and in many ways more complex than what is experienced during
development of a drug intended for a larger patient population.
The complexities can range from
 Scientific
 Ethical
 operational
 Financial

26. 26
Due to these hurdles, the need for life-saving orphan drugs remains high while
availability remains comparatively low.
Developing drugs or biological products for rare diseases or conditions that affect a
small number of people is always demanding.
 Small patient populations: This makes it difficult to find and recruit
enough patients for clinical trials, to generate sufficient data on safety and
efficacy, and to justify the high costs of research and development.
 Limited knowledge and awareness: There is often a lack of scientific
understanding of the mechanisms and natural history of rare diseases, as
well as a lack of awareness among the general public and medical
professionals. This hampers the diagnosis, prevention and treatment of rare
diseases, and the identification of potential drug targets and biomarkers.
 Regulatory uncertainties: There is often a lack of clear and consistent
guidance and incentives from regulatory authorities on how to conduct
orphan drug development, especially in regions or countries that do not have
specific orphan drug legislation or policies. This creates challenges in
designing and conducting clinical trials, obtaining marketing authorization,
and ensuring access and affordability of orphan drugs.
 Pricing and reimbursement issues: Orphan drugs tend to be very
expensive due to the high costs of research and development, the small
market size, and the need to recover the investment. However, many
healthcare systems are not able to afford or willing to pay for these high-
priced drugs, which limits the availability and accessibility of orphan drugs
for patients who need them.

27. 27
 Access and affordability : once approved orphan drugs may be expensive
and less access to these treatments can be a concern for patients and
healthcare system
 Challenges in end point biomarkers : determining appropriate clinical
trials endpoints and biomarkers for rare diseases can be complicated
impacting design of the clinical trials
 lack of natural history and data : rare diseases often lack comprehensive
natural history data, which is crucial for understanding disease progression
and desigining clinical trials.

28. 28
Comparison of the four FDA expedited programes
Expedited
programme
Type Effect
Priority review Designation Reduces time of application review process from 10 to
6 months of priority regulatory review
Breakthrough
therapy
Designation Expedites review of drugs that may show substantial
improvement for patients with serious diseases over
existing drugs
Fast track Designation Expedites drug development and review to treat serious
conditions and fill unmet medical need
Accelerated
approval
Approval
pathway
Permits use of surrogate or intermediate clinical
endpoint for filling an unmet medical need for serious
conditions

29. 29
7.APPROVALS
Fig.no 4 process of approval

30. 30
Fig.no 5 comparison of orphan drug approvals and designations
According to pdufa
Prescription Drug User Fee Act (PDUFA) dates refer to deadlines for the FDA to
review new drugs. The PDUFA date is 10 months after the drug application has
been accepted by the FDA or 6 months, if the drug is given a priority review
designation.

31. 31
Recent approvals
PDUFA
Date
Orphan
Drug
Indication Company Status
1.20.2023 Zanubritinib CLL/SLL Beigene APPROVED
1.27.2023 Jaypirca
Mantle cell
lymphoma
Lilly APPROVED
2.4.2023
TAKHZYRO
(lanadelumab-
flyo)
Prevent
attacks of
hereditary
angioedema
(HAE)
Takeda APPROVED
2.11.2023 Aflibercept
Retinopathy
of
Prematurity
(ROP) in
preterm
infants
Regeneron APPROVED
2.16.2023 Lamzede
Alpha-
mannosidosis
Chiesi APPROVED
The Prescription Drug User Fee Act (PDUFA) was a law passed by the United
States Congress in 1992 which allowed the Food and Drug Administration (FDA)
to collect fees from drug manufacturers to fund the new drug approval process.

32. 32
8.REFERENCE
1. Orphan Drug Act of 1983, Pub. L. No. 97–414, 96 Stat 2049 (Jan. 4, 1983). §
526(a)(2).
2. Fellows GK, Hollis A. Funding innovation for treatment for rare diseases:
adopting a cost-based yardstick approach. Orphanet Journal of Rare Diseases.
2013;8:180 10.1186/1750-1172-8-180 [PMC free article] [PubMed]
[CrossRef] [Google Scholar]
3. Waxman HA. The history and development of the Orphan Drug Act In:
Scheinberg IH, Walsh JM, editors. Orphan Diseases and Orphan Drugs.
Manchester University Press; 1986. [Google Scholar]
4. Seoane-Vazquez E, Rodriguez-Monguio R, Szeinbach SL, Visaria J. Incentives
for orphan drug research and development in the United States. Orphanet J
Rare Dis. 2008 Dec 16;3:33. [PMC free article] [PubMed]
5. Ariyanchira S. Global Markets for Orphan Drugs, BCC Research, BCC00191,
PHM038B, January 2007. Available
from: http://www.bccresearch.com/report/PHM038B.html [last accessed on
2010 Jul 26]
6. Shah RR. Regulatory framework for the treatment of orphan diseases.
Available
from: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=fabryandpart=A74
5 [last accessed on 2010 Jul 25]

33. 33
7. "Rare Diseases". Siope.Eu. 9 June 2009. Archived from the original on 3
December 2012. Retrieved 24 September 2013
8. "Useful Information on Rare Diseases from an EU Perspective" (PDF).
European Commission. Retrieved 19 May 2009