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8
Variations to the Drug Authorisation Process
8.1 Chapter Introduction
The previous chapters examined the process for development and authorisation of a
drug product containing a new active ingredient. This represents the most tortuous
path to market for any medicinal product. This chapter looks at the variations to
the authorisation process that can apply depending on the nature of the product
or its intended use. These include incentives for orphan drugs and paediatric
applications, alterations or extensions to existing approved drug products and
authorisation of generic copies or biosimilar versions of approved drugs, and other
special authorisation procedures.
8.2 Provisions in Support of Special Drug Applications
The regulations contain certain incentives and provisions to encourage and support
the development of drugs for treatment of certain categories of disease or condition
or that target particular population cohorts. Principal among these are Orphan Drug
regulations, which are intended to encourage the development of drugs for rare dis-
eases, and the Paediatric regulations which specic studies on their suitability for
children.
8.2.1 Orphan Drugs
Products intended to treat rare diseases or conditions, which, considering the size
of the target market are not commercially attractive, may be categorised as Orphan
drugs. In Europe for example, it is estimated that 1 in 17 citizens has a rare disease
and over 6,000 such rare diseases have thus far been identied. Incentives to encour-
age the development of such products were introduced in the US in 1983 with the
enactment of the Orphan Drug Act. It was not until Regulation (EC) No. 141/2000
and Regulation (EC) No. 847/2000 were adopted that the EU provided similar
incentives.
Medical Product Regulatory Aairs: Pharmaceuticals, Diagnostics, Medical Devices,
Second Edition. John J. Tobin and Gary Walsh.
© 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.
166 8 Variations to the Drug Authorisation Process
To avail of the incentives, the sponsor must rst of all request that the drug is
designated as an orphan product by the relevant authorities, the Committee for
Orphan Medicinal Products (COMP) in the EU and the Oce of Orphan Products
Development (OOPD) in the US. It is important to note that designation of orphan
status is not a market authorization. Drugs (chemical and biologics) designated as
orphan drugs must subsequently be assessed as per standard regulatory procedures
to gain marketing approval. For example, in Europe, all orphan drugs must be
assessed for marketing authorisation via the EMAs centralized authorisation
procedure.
The criteria on which orphan status is granted dier slightly between the EU and
the US. In Europe, consideration is given to the nature and prevalence of the disease,
the commercial attractiveness and the availability of existing therapies, whereas US
designations are just based on incidence and commercial viability. The specic des-
ignation criteria are shown in Figure 8.1. The US authorities will accept a specic
paediatric application as aplausible subset for orphanstatus designation, which may
be granted separate from the overall drug status.
Market exclusivity (the regulatory authorities will not approve a similar product
for the same indication) has proved to be the most signicant benet that can be
gained from obtaining orphan status. This is intended to provide the sponsor with a
marketing window to recover the costs of the development. In Europe, the authori-
ties will not grant authorisation to similar drugs for the same therapeutic indication
for a period of 10 years after approval of the rst drug, unless:
EU Orphan Drug Criteria
A medicinal product shall be designated as an orphan medicinal product if its sponsor can
establish:
(a) that it is intended for the diagnosis, prevention or treatment of a life-threatening or
chronically debilitating condition aecting not more than ve in 10 thousand per-
sons in the Community when the application is made,
or
that it is intended for the diagnosis, prevention or treatment of a life-threatening,
seriously debilitating or serious and chronic condition in the Community and that
without incentives it is unlikely that the marketing of the medicinal product in the
Community would generate sucient return to justify the necessary investment;
and
(b) that there exists no satisfactory method of diagnosis, prevention or treatment of the
condition in question that has been authorised in the Community or,if such method
exists, that the medicinal product will be of signicant benet to those aected by
that condition.
US Orphan Drug Criteria (Rare Disease)
‘rare disease or condition’ means any disease or condition which
(a) aects less than 200,000 persons in the United States,
or
(b) aects more than 200,000 in the United States and for which there is no reasonable
expectation that the cost of developing and making available in the United States a
drug for such disease or condition will be recovered from sales in the United States
of such drug.
Figure 8.1 Criteria for designation as an Orphan Drug.
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8.2 Provisions in Support of Special Drug Applications 167
● The holder of the marketing authorization for the original orphanmedicinal prod-
uct gives consent.
● The new drug can be shown to be clinically superior.
● The holder of the marketing authorization for the original orphan product is
unable to supply sucient quantities of the medicinal product.
(‘Similar’ drugs include active ingredients with the same principal molecular struc-
tures and mechanism of action but with possible variation due to isomerism, salts,
complexes, conjugates, or minor structural alteration)
The FDA will not approve other versions of the product for orphan designated use
for a period of seven years after the rst approval unless:
● The FDA revokes the orphan designation.
● The marketing application for the drug is withdrawn.
● The holder of the exclusive approval gives consent.
● Failure of the holder of exclusive approval to assure availability of a sucient
quantity of the drug.
Financial and other benets are also available during the development of the drug.
Sponsors in the US may receive tax credits of up to 50% against expenses incurred in
clinical trials. Grant aid is available in both the US and EU to support research into
the development of Orphan drugs. The regulatory agencies will also provide assis-
tance in developing clinical trial protocols since well-designed trials are essential in
a situation where there may be limited availability of trial subjects. The OODP acts
as a coordinating ombudsman to facilitate ecient review by the relevant centre.
In Europe, allapplications for orphan designation are reviewedby the COMP, which
must conclude its review within 90 days. The EMA then sends the COMP opinion
to the European commission, which is the body responsible for actually granting
orphan designation. Finally, sponsors in the US are exempt from the Prescription
Drug User Fees that are normally paid to the FDA for regulatory reviews. In Europe,
the EMA will grant a rebate on the application fee, depending on the availability of
funds in the budget specically allocated by the Commission for this purpose.
Both the European Commission and the FDA maintain (publically accessible) reg-
isters of approved orphan-statusdrugs within their regions.Some exemplar products
granted orphan status and subsequently approval for medical use in the US arelisted
in Table 8.1.
8.2.2 Paediatric Applications
In the US, paediatric drug development is primarily dictated by:
● The Pediatric Research Equity Act (PREA).
● Best Pharmaceuticals for Children Act (BPCA).
● Title V of FDA Safety and Innovation Act (FDASIA).
US regulations require, that by default, the sponsor must specically assess the
safety and eectiveness of a drug in paediatric patients (usually dened as children
ranging from 0 to 16 years of age). However, waivers will be granted if it can be jus-
tied that the drug does not have meaningful therapeutic application in children,
or is unlikely to have benet over existing therapies, or where it is not possible to
Table 8.1 Some exemplar products granted orphan status and subsequently approval for medical use in the US.
Name Orphan designation
Orphan
designation
date
Marketing
approval
date
Exclusivity
end Approved labelled indication Exclusivity protected indication
Alirocumab Treatment of
homozygous familial
hypercholesterolemia
06/15/2017 04/01/2021 04/01/2028 as an adjunct to other
LDL-C-lowering therapies in
adult patients with
homozygous familial
hypercholesterolemia (HoFH)
to reduce LDL-C
as an adjunct to other
LDL-C-lowering therapies in
adult patients with
homozygous familial
hypercholesterolemia (HoFH)
to reduce LDL-C
Botulinum toxin
type A
Treatment of dynamic
muscle contracture in
pediatric cerebral palsy
patients
12/06/1991 06/20/2019 06/20/2026 BOTOX is indicated for the
treatment of upper limb
spasticity in pediatric patients
2 to 17 years of age
For the treatment of upper
limb spasticity in pediatric
cerebral palsy patients 2 to
17 years of age
Deazacort Treatment of
Duchenne muscular
dystrophy
08/16/2013 06/07/2019 06/07/2026 EMFLAZA is indicated for
the treatment of Duchenne
muscular dystrophy (DMD)
in patients two years of age
and older
For the treatment of Duchene
muscular dystrophy in
patients two years of age to
less than ve years of age
Eculizumab Treatment of
neuromyelitis optica
06/24/2013 06/27/2019 06/27/2026 Soliris is indicated for the
treatment of neuromyelitis
optica spectrum disorder
(NMOSD) in adult patients
who are anti-aquaporin-4
(AQP4) antibody positive
For the treatment of
neuromyelitis optica
spectrum disorder (NMOSD)
in adult patients who are
anti-aquaporin-4 (AQP4)
antibody positive
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Lenalidomide Treatment of follicular
lymphoma
09/17/2013 05/28/2019 05/28/2026 REVLIMID in combination
with a rituximab product is
indicated for the treatment of
adult patients with previously
treated follicular lymphoma
(FL)
In combination with a
rituximab product for the
treatment of adult patients
with previously treated
follicular lymphoma (FL)
Mitomycin Treatment of upper
tract urothelial cell
cancers (transitional
cell carcinoma of the
renal pelvis and ureter)
09/08/2014 04/15/2020 04/15/2027 JELMYTO
TM
is indicated for
the treatment of adult
patients with low-grade
Upper Tract Urothelial
Cancer (LG-UTUC)
Indicated for the treatment of
adult patients with low-grade
Upper Tract Urothelial
Cancer (LG-UTUC)
Pembrolizumab Treatment of Stage IIB
through IV malignant
melanoma
11/19/2012 02/15/2019 02/15/2026 KEYTRUDA is indicated for
the adjuvant treatment of
patients with melanoma with
involvement of lymph node(s)
following complete resection
KEYTRUDA is indicated for
the adjuvant treatment of
patients with melanoma with
involvement of lymph node(s)
following complete resection
Risdiplam Treatment of spinal
muscular atrophy
01/04/2017 08/07/2020 08/07/2027 treatment of spinal muscular
atrophy (SMA) in patients
two months of age and older
treatment of spinal muscular
atrophy (SMA)
Triclabendazole Treatment of
fascioliasis
04/17/2017 02/13/2019 02/13/2026 EGATEN
TM
is indicated for
the treatment of fascioliasis in
patients six years of age and
older
EGATEN is indicated for the
treatment of fascioliasis in
patients six years of age and
older
170 8 Variations to the Drug Authorisation Process
undertake studies because of the number of available patients. A paediatric appli-
cation may be submitted separately, subject to FDA agreement. As an incentive to
industry, drugs with specic paediatric indications for use are granted six months of
extra market exclusivity over the standard terms that would otherwise apply.
Paediatric legislation was introduced in the European Union under regulations
EC/1901/2006 and EC1902/2006. This requires that marketing authorisation appli-
cations for new drugs must be accompanied by either the results of specic stud-
ies demonstrating safety and eectiveness in the paediatric populations (usually
dened as children up to the age of 18 years) or waivers or deferrals granted by the
European Medicines Agency.
An EMA guideline on pharmaceutical development of medicines for paediatric
use was published in 2013 and provides further guidance on the subject.
The EMA’s Paediatric committee (PDCO) has been established to provide advice
on paediatric issues, to adopt opinions on paediatric investigation plans (PIPs),
which must now be submitted to the agency before commencing the studies, and
to grant deferrals or waivers where appropriate. The committee will also assist in
reviewing the paediatric section of a marketing authorisation application. As an
incentive to undertake an agreed paediatric investigation plan (PIP), manufacturers
may gain additional market protection ranging from six months to two years in the
case of an orphan medical product. It is also possible for manufacturers of existing
drugs that no longer enjoy any protection to submit new ‘paediatric use’ marketing
authorisation applications and thus obtain the data/market exclusivity periods
associated with a standard authorisation. Provision is also made for nancial aid to
conduct research and development of paediatric drugs.
8.3 Accelerated Access to New Drug Therapies
The time required for fully establishing the safety and ecacy of a new drug in the
eyes of the regulatory authority might not always be to the benet of the proposed
patient group. This is particularly so in the case of drugs intended to treat serious or
life-threatening diseases where no eective therapy currently exists. Various provi-
sions have been incorporated into the regulations to allow accelerated access to such
therapies.
8.3.1 EMA Accelerated Review and Conditional Marketing Routes
In Europe, a sponsor may request an accelerated review of a (standard) marketing
authorisation application by the EMA on grounds that the product is of major inter-
est to public health, particularly from the viewpoint of therapeutic innovation. If
granted, an accelerated review must be conducted within 150 days as opposed to the
210 days allowed for a standard technical assessment.
European Regulation (EC)No. 726/2004 (as further elaborated in Regulation (EC)
No. 507/2006) provides a basis for the granting of a conditional marketing authori-
sation to medicines in specic circumstances. Its scope incorporates:
● Medicinal products which aim at the treatment, the prevention or the medical
diagnosis of seriously debilitating diseases or life-threatening diseases,
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8.3 Accelerated Access to New Drug Therapies 171
● Medicinal products to be used in emergency situations, in response to public
health threats duly recognised either by the World Health Organisation or by the
EU itself and
● Medicinal products designated as orphan medicinal products.
Conditional marketing authorisation is, in eect, granted for such medicinal prod-
ucts on less comprehensive clinical data than would normally be required, in the
interests of public health, where the benet of immediate availability outweighs the
inherent risk. The EMA’s CHMP may grant a conditional marketing authorisation
if it nds that the product meets all of the following criteria:
● The benet–risk balance of the medicine is positive,
● It is likely that the applicant will be able to provide comprehensive data post-
authorisation,
● The medicine fulls an unmet medical need and
● The benet of the medicine’s immediate availability to patients is greater than the
risk inherent in the fact that additional data are still required.
Such authorizations are valid for one year and can be renewed. Their approval
is usually contingent upon the authorization holder generating additional data,
providing greater assurance of a positive risk: benet balance, and which can lead
to conversion of conditional authorization to a standard marketing authorisation.
8.3.2 EU Compassionate Use
EU Member States may also permit access to non-approved drugs on compassion-
ate grounds so that patient groups who suer from chronic, seriously debilitating,
or life-threatening diseases for which no satisfactory authorised drugs exist, may
receive treatment while the drug is still undergoing clinical trials or awaiting mar-
keting authorisation. The Member State must inform the EMA if such use is con-
templated. After consideration, the CHMP may issue recommendations on the con-
ditions of use, distribution or patient groups targeted.
8.3.3 Expedited Pathways in the US
In the US, the FDA operates four programs that expedite the development and
review of new drugs specically being developed to address unmet medical need(s)
in the treatment of a serious or life-threatening conditions. These programs/
pathways are:
● Fast track designation.
● Breakthrough therapy designation.
● Accelerated approval.
● Priority review designation.
Table 8.2 provides a summary overview of such programmes. Each has their own
qualifying criteria and a drug in development may meet the criteria set for morethan
one of these pathways.
Table 8.2 Comparison of FDA’s Expedited Programs for Serious Conditions, as presented in the FDA publication ‘Guidance for Industry Expedited
Programs for Serious Conditions – Drugs and Biologics’.
Fast track Breakthrough therapy Accelerated approval Priority review
Nature of
program
Designation Designation Approval pathway Designation
Reference Section 506(b) of the FD&C
Act, as added by section 112
of the Food and Drug
Administration
Modernization Act of 1997
(FDAMA) and amended by
section
901 of the Food and Drug
Administration Safety and
Innovation Act of 2012
(FDASIA)
Section 506(a) of the
FD&C Act, as added by
section 902 of FDASIA
21 CFR part 314, subpart H 21
CFR part 601, subpart E Section
506(c) of the FD&C Act, as
amended by section 901 of
FDASIA
Prescription Drug User Fee Act
of 1992
Qualifying
criteria
A drug that is intended to
treat a serious condition AND
nonclinical or clinical data
demonstrate the potential to
address unmet medical need
OR A drug that has been
designated as a qualied
infectious disease product
A drug that is intended to
treat a serious condition
AND preliminary clinical
evidence indicates that the
drug may demonstrate
substantial improvement
on a clinically signicant
endpoint(s) over available
therapies
A drug that treats a serious
condition AND generally
provides a meaningful advantage
over available therapies AND
demonstrates an eect on a
surrogate endpoint that is
reasonably likely to predict
clinical benet or on a clinical
endpoint that can be measured
earlier than irreversible
morbidity or mortality (IMM)
that is reasonably likely to
predict an eect on IMM or other
clinical benet (i.e. an
intermediate clinical endpoint)
An application (original or
Ecacy supplement) for a drug
that treats a serious condition
AND, if approved, would provide
a signicant improvement in
safety or eectiveness OR: Any
supplement that proposes a
labelling change pursuant to a
report on a pediatric study under
505Ab OR: An application for a
drug that has been designated as
a qualied infectious disease
product OR: Any application or
supplement for a drug submitted
with a priority review voucher
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When to
submit request
With IND or after.
Ideally, no later than the
pre-BLA or pre-NDA meeting
With IND or after.
Ideally, no later than the
end-of-phase 2 meeting
The sponsor should ordinarily
discuss the possibility of
accelerated approval with the
review division during
development, supporting, for
example, the use of the planned
endpoint as a basis for approval
and discussing the conrmatory
trials, which should usually be
already underway at the time of
approval
With original BLA, NDA or
ecacy supplement
Timelines for
FDA response
Within 60 calendar days of
receipt of the request
Within 60 calendar days of
receipt of the request
Not specied Within 60 calendar days of
receipt of original BLA, NDA, or
ecacy supplement
Features Actions to expedite
development and review.
Rolling review
Intensive guidance on
ecient drug
development.
Organizational
commitment.
Rolling review.
Other actions to expedite
review
Approval based on an eect on a
surrogate endpoint or an
intermediate clinical endpoint
that is reasonably likely to
predict a drug’s clinical benet
Shorter clock for review of
Marketing application (6 months
compared with the 10-month
standard review)
Additional
considerations
Designation may be rescinded
if it no longer meets the
qualifying criteria for fast
track
Designation may be
rescinded if it no longer
meets the qualifying
criteria for breakthrough
therapy
Promotional materials.
Conrmatory trials to verify and
describe the anticipated eect on
IMM or other clinical benets.
Subject to expedited withdrawal
Designation will be assigned at
the time of original BLA, NDA or
ecacy supplement ling
174 8 Variations to the Drug Authorisation Process
For example, drugs that are intended to treat serious or life-threatening diseases
and that demonstrate potential meaningful therapeutic benets over existing treat-
ments may be considered under the accelerated approval pathway. The FDA will
then take appropriatemeasures to facilitate the development and accelerated review
of such products. The FDA may grant an approval on the basis of clinical trials
that demonstrate eects on surrogate endpoints or clinical indicators (e.g. a lab-
oratory measurement, radiographic image, physical sign or other measure that is
believed to predict clinical benet), without having to wait for conrmation of the
nal therapeutic eect (e.g. prevention of morbidity). Approvals are usually condi-
tional on the sponsor continuing the trials to fully validate the therapy. Such studies
are termed phase four conrmatorytrials.If these trial(s) conrm actual clinicalben-
et, the productis then granted atraditional approval. If the conrmatory trial(s) fail
to demonstrate actual clinical benet, the FDA can initiate regulatory procedures
leading to product removal from the market.
8.3.4 Expanded Access and Emergency Use Authorization (EUA)
Expanded access (“compassionate use”) is an FDA mechanism that facilitates the
application of an investigational new drug outside of a clinical trial context, to treat
patients with serious or immediately life-threatening diseases orconditions when no
satisfactory authorised therapy exists. Drug administration must follow a treatment
protocol submitted to the FDA as part of the IND application. Treatment INDs are
usually only granted whilethe drug is undergoing Phase III clinical trials or the NDA
evaluation and authorisation stage.
Emergency Use Authorization (EUA) is a US mechanism, underpinned by section
564 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), facilitating emer-
gency introduction of medical countermeasures against chemical, biological, radi-
ological, and nuclear (CBRN) threats, including infectious diseases. The process is
triggered only when the Secretary of HHS (Department of Health and Human Ser-
vices) declares that an EUA is an appropriate response to a public health emergency.
This in turn allows the FDA to consider and authorize unapproved medical products
(or unapproved uses of approved medical products) for the diagnosis, treatment,
or prevention of serious or life-threatening diseases or conditions caused by the
threat. In recent times, EUAs have underpinned the rapid approval of COVID-related
drug and vaccine products (Box 8.1), as well as COVID diagnostic agents.
Box 8.1 Rapid Regulatory Approval of Covid-19 Medicines
Following the initial reports of Covid-19 emanating from Wuhan, China in
December 2019, the first known cases of the disease in the US and Europe were
recorded on January 21st and 24th, 2020, respectively. Regulatory and allied
agencies worldwide responded by developing and/or implementing emergency
response plans to facilitate and enable the timely assessment and approval of
Covid-19 medicines. Actions included:
● Prioritization of resources toward covid-19 related issues and activities.
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