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8.4 Approval of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible 175
● Enhanced and rapid communication/coordination between all stakeholders.
● Provision of rapid scientific advice and compliance checks to product devel-
opers.
● Accelerated assessment/evaluation procedures including rolling reviews (i.e.
the assessment of data being generated to support product approval as the
data is generated rather than waiting to assess all the data as part of a final-
ized marketing application).
While regulatory authorities expedited product development, assessment,
and approval in every way they could, it is worth noting that core activi-
ties/regulatory procedures applied were those already provided for under
relevant pharmaceutical/healthcare laws and guidelines. Thus FDA product
approvals were invariably made via the EUA pathway and included:
● Pfizer-BioNTech COVID-19 Vaccine (Comirnaty) (EUA first issued December
11th 2020)
● Moderna COVID-19 Vaccine (EUA first issued December 18th 2020).
● Janssen COVID-19 Vaccine (EUA first issued February 27th 2021).
● Remdesivir (EUA first issued May 1st 2020).
● REGEN-COV (Casirivimab and Imdevimab) (EUA first issued November 21st
2020)
● Bamlanivimab and Etesevimab (EUA first issued February 9th 2021).
Within the European Union, the ‘conditional marketing authorisation’ procedure
was used to expedite the approval of COVID-19 vaccines and treatments,
including:
● Comirnaty (Pfizer-BioNTech COVID-19 Vaccine; Conditional Approval, Decem-
ber 21st 2020).
● Spikevax (previously COVID-19 Vaccine Moderna, Conditional approval, Jan-
uary 6th 2021).
● Vaxzevria (previously COVID-19 Vaccine AstraZeneca, Conditional Approval,
January 29th 2021).
● COVID-19 Vaccine Janssen (Conditional approval awarded March 11th 2021).
● Veklury (remdesivir, Conditional Approval July 3rd, 2020).
8.4 Approval of New Drugs When Human Efficacy
Studies Are Not Ethical or Feasible
us regulations (CFR, Part 314) recognise that trials with human subjects may not
be ethical for drugs intended to prevent or ameliorate serious or life-threatening
conditions caused by exposure to lethal or permanently disabling toxic, biological,
chemical, radiological, or nuclear substances. In such circumstances, the FDA
may approve applications based on well-designed safety and ecacy studies in
animals only.
176 8 Variations to the Drug Authorisation Process
EU legislation also addresses this issue through its facility to award a ‘marketing
authorization under exceptional circumstances’. Its legal basis is grounded in Reg-
ulation (EC) No. 726/2004. Authorization under exceptional circumstances can be
considered if the applicant can demonstrate an inability to provide comprehensive
safety and ecacy data under normal conditions of use, because:
● The indications for which the product is intended are encountered so rarely that
the applicant cannot reasonably be expected to provide comprehensive evidence,
● In the present state of scientic knowledge, comprehensive information cannot
be provided and
● It would be contrary to generally accepted principles of medical ethics to collect
such information.
Marketing authorisation under exceptional circumstancesalsorequires the autho-
rization holder to pursue enhanced post-approval pharmacovigilance activities.
8.5 Animal Drugs for Minor Use and Minor Species
The Minor Use and Minor Species (MUMS) amendments to the FD&C Act (Sections
571, 572, 573) weresigned into US law in 2004.Their purpose is tomakedrugs legally
available for use in minor species or for treatment of rare diseases in major species.
Major animal species are dened as cattle, horses, swine, chickens, turkeys, dogs,
and cats. All other species are considered minor species. A drug developer can ben-
et from MUMS provisions in one of three ways.
8.5.1 Conditional Approval
The developer may receive conditional approval for up to ve years, through annual
renewals, on the basis that the safety has been established,but that complete ecacy
data will only be generated during the conditional approval period. The labelling
must bear the statement ‘conditionally approved by FDA pending a full demonstra-
tion of eectiveness under application number’.
8.5.2 Indexing
In certain cases, such as the treatment of zoo animals or endangered species, it may
be impossible to recover the cost of approval of a drug for that species. In such cir-
cumstances, the FDA can add the drug toan index of legally marketed non-approved
drugs. A drug can only be indexed for use in situations where there is no risk of it
entering the human food chain.
8.5.3 Designation
A developer may apply tohaveanew drug designated. Designation entitlesthedevel-
oper to avail of the same type ofincentives in terms of support and market exclusivity
that apply to human orphan products.
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8.8 EU System for Processing Changes 177
8.6 Special Provisions to Facilitate Access to Drugs
for Animal Treatment in the EU
The EU regulations permit veterinarians to treat animals with animal drugs
that have not been authorised for that species, or alternatively to use human
drugs, in situations where there is no authorised drug for treatment of the con-
dition in the species. Moreover, Regulation (EU) 2019/6 on veterinary medicinal
products, which came into force in January 2022, makes provision for prod-
uct authorizations based on limited safety and ecacy datasets in exceptional
circumstances, if the benet of the availability of the market of the veterinary
medicinal product to the animal or public health outweighs the risks inherent in
not having complete datasets and if the products are intended for use in a limited
market.
8.7 Changes to an Authorised Drug
The regulatory authorities must be informed of all changes relating to an authorised
drug. The procedure for processing changes will vary depending on the magnitude
of the change. Prior authorisation is generally required for changes designed to alter
the drug product or extend its therapeutic use (i.e. changes to the active ingredients,
strength, form, route of administration, dosage regimen, or therapeutic indication),
or manufacturing changes that have the potential to signicantly alter the safety
or ecacy of the product. Notication is usually sucient for other minor changes
that are unlikely to have an adverse eect on the safety or ecacy of the product.
Dierent approaches to the categorisation and procedures for processing changes
apply in Europe and the US.
8.8 EU System for Processing Changes
A variation is a change to the terms of a marketing authorisation and changes in
the EU may be categorised as Extensions, Major Variations (Type II variations), or
Minor Variations (Type IA or IB). All variations or extensions relating to the basic
active ingredient are considered part of the same “global” marketing authorisation.
European Commission Regulation (EC) No 1234/2008 outlines the procedures
for processing variations to marketing authorisations granted via both National
and Centralised procedures. The Annexes to the regulation provide criteria for
categorisation of changes. The Commission has also published guidelines (2013/C
223/01) aimed at assisting regulation applications. The up-to-date application
form for variation to a marketing authorisation for medicinal products (human
and veterinary) to be used in the mutual recognition and the centralised proce-
dures are published as part of Eudralex volume 2b, available on the commission’s
website.
178 8 Variations to the Drug Authorisation Process
8.8.1 Extension Applications
Extension Applications are applicable to the following changes, which are further
detailed in Annex I of EC 1234/2008:
● Changes to the active substance(s), such as use of dierent salts, complexes, iso-
mers, or slightly dierent biological materials,
● Changes to strength, pharmaceutical form, or route of administration and
● Other changes specic to veterinary medicinal products to be administered to
food-producing animals: change or addition of target species.
An exception to the above general criteria is changes to the active component
of vaccines against human inuenza, human coronavirus, equine inuenza, avian
inuenza, foot-and-mouth disease, or bluetongue, which can be processed using a
Type II Variation application even though it involves a change in the active sub-
stance. Moreover, under circumstances where a human inuenza or coronavirus
pandemic occurs, the European Commission may exceptionally and temporarily
accept a variation to the terms of a marketing authorisation for a vaccine, even if
certain non-clinical or clinical data are missing.
Extension applications are processed in accordance with the standard procedures
for granting a marketing authorisation. Applications must be submitted to the
EMA (Union authorised drugs) or Member State Competent Authorities (National
authorisations) as appropriate, together with a dossier containing new information
supporting the extension. The applicant can refer to the original dossier for other
information relevant to the extension.
8.8.2 Major Variation (Type II)
A Major or Type II Variation applies to any change that is not categorised as either
an Extension or a Minor Variation. Type II variations incorporate:
● the addition of a new therapeutic indication or modication of an existing one,
● signicant modications of the summary of product characteristics due in partic-
ular to new quality, pre-clinical, clinical or pharmacovigilance ndings,
● changes outside therangeof approved specications, limits, or acceptancecriteria,
● substantial changes to the manufacturing process (or site), formulation, speci-
cations, or impurity prole of the active substance or nished medicinal product
which may have a signicant impact on the quality, safety, or ecacy ofthe medic-
inal product,
● variations related to modications in the manufacturing process or sites of the
active substance for a biological medicinal product,
● the introduction of a new design space or the extension of an approved one,
● a change to or addition of a non-food-producing target species,
● changes to the withdrawal period for a veterinary medicinal product and
● changes to the active substance for vaccines against human inuenza, human
coronavirus, equine inuenza, avian inuenza, foot-and-mouth disease or
bluetongue.
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8.9 Processing Changes in the US 179
Applications must be submitted to the EMA in the case of drugs that hold a Union
authorisation or to the all the Competent Authorities of Member States where the
drug is authorised in the case of drugs that were authorised by national Competent
Authorities. Applications must be accompanied by relevant documents and data
in support of the variation. Variations in the indications for use shall be supported
by clinical and preclinical data if justied. The relevant EMA committee or the
reference Member State as appropriate must deliver an opinion within 60 days of
verication that the application has been submitted correctly. This period may be
extended to 90 daysin the case ofa change to or addition of therapeuticindications, a
change to or addition of a non-food producing target species, or changes to the active
substance for vaccines against equine inuenza, avian inuenza, foot-and-mouth
disease or bluetongue, but this still represents a substantially shorter review period
than is allowed for a standard marketing authorisation or extension application.
Concerned Member States have 30 days to recognise the opinion of the reference
Member State, while the Commission must update a Union decision in accordance
to centralised procedures. Shorter reviewperiods (45 or 55 days) apply to uvaccines
that follow this procedure, while urgent safety restrictions may be processed within
24 hours.
8.8.3 Minor Variation (Type IA or IB)
Variations classied as minor include changes in the name and address of a
marketing authorisation holder, manufacturing sites, batch size, test procedures,
specications, excipients, shelf life, packaging or labeling. The individual varia-
tions are categorised as either Type IA, which involve changes considered not to
impact the quality, safety, or ecacy of the medicinal product or Type IB, which
could impact the product. For a Type IA variation, the marketing authorisation
holder may proceed with the change provided they notify the authorities within
12 months of implementing the change. In the case of a Type 1B variation, the
marketing authorisation holder must notify the authorities before enacting the
change. The authorities are allowed 30 days to consider a valid Type 1B notication,
during which period they must inform the holder of any objections. Otherwise,
the variation may be introduced once the 30 days have elapsed.
8.9 Processing Changes in the US
The procedure for introducing changes to an approved drug in the US is dictated
by the type of data that must be submitted to support the alteration. Changes
that require review of new investigations to approve the modication, other than
bioavailability or bioequivalence studies, must be submitted as supplementary
NDA’s/NADA’s, as they are viewed as new drugs, meaning that are not generally
recognised (by the FDA) as safe and eective for the indications proposed. These
include changes to the active ingredient, pharmaceutical form, strength, or route of
administration of the drug product, or alterations to the dosage regimen, or addition
180 8 Variations to the Drug Authorisation Process
of new therapeutic indications for use. The requirement to submit a new therapeutic
use using new drug approval procedures diers from the EU system where it can be
processed as a Major variation. The applicant is only required to submit new data
that supports the modication and can refer to the original submission for other
relevant data, provided they are the owner or have obtained a right of reference.
8.9.1 Manufacturing Change Supplements
Changes to manufacturing processes,specications, manufacturing sites, orpackag-
ing, that have the potential to have an adverse eect on the identity, strength, quality,
purity, or potency of the drug product or labelling, or other miscellaneous changes
that might otherwise inuence the safety or eectiveness of the drug, must be noti-
ed as manufacturing change supplements. While such changes are not intended
to signicantly alter the drug or extend its use, the magnitude of potential eects
dictates how these supplements are categorised and processed. The FDA has issued
specic guidance for industry to assist in selecting the appropriate supplement cat-
egory. In each case, the approved drug holder must submit sucient evidence and
information to enable the FDA understand and assess the impact of the proposed
change.
8.9.2 Major Changes
Major changes require review and prior approval by the FDA before they can be
implemented. Examples of changes that would be considered major include the
following:
● Quantitative or qualitative changes to the drug product,
● Changes that may aect product sterility,
● Changes to the synthesis or manufacturing process that may aect the impurity
prole,
● Changes that require bioequivalence validation and
● Changes to labelling resulting from post-approval studies.
8.9.3 Moderate Changes
There are two categories of moderate changes that can be submitted to the FDA,
‘changes being eected in 30 days’ and ‘changes being eected’. The applicant
must wait for 30 days before implementing a 30 days change whereas a change
being eected can be implemented once the FDA has been notied. Changes that
would be considered suitable for a 30 days notication supplement include the
following:
● Changes to a closure system that does not aect quality of the drug product,
● Changes in nal process scale involving new equipment and
● Relaxation of acceptance criteria or deletion of tests in accordance with ocial
compendia.
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8.10 Authorisation of Generic Drugs 181
Immediate changes may include the following:
● Changes to specications or test methods intended to provide increased assurance
as regard product quality,
● Changes to the size or shape of a container for a non-sterile drug and
● Changes to labelling to strengthen statements on contraindications, precautions,
overdose, administration, etc.
8.9.4 Minor Changes
Minor changes do not have to be notied to the FDA by a specic supplement, but
may be included in the next annual report. Minor changes would include editorial
corrections to labelling, deletion or reduction in an ingredient intended to aect the
colour, replacement of equipment with similar equipment, or extension of shelf life
based on real-time data.
8.10 Authorisation of Generic Drugs
Once the patent protection on an authorised new drug has expired, other manu-
facturers may wish to introduce generic copies of the drug. The new manufacturer
must apply for a marketing authorisation for the generic drug. However, the appli-
cant will not have to submit preclinical and clinical data, if bioequivalence with
the approved reference drug can be demonstrated (demonstrating bioequivalence
entails illustrating that two products are pharmaceutically equivalent to each
other). The authorities will authorise the generic copies on the basis that the safety
and ecacy established for the reference drug will also apply to the copy when both
versions of the drug display similar bioavailability proles. While this strategy may
appear to oer an unfair advantage to the generic manufacturer, there are a number
of reasons why it is in the interest of public health. The authorities do not have to
waste time reviewing replicate pre-clinical and clinical data and instead are able
to allocate more of their resources to the review of new drugs, which benets the
innovator who will be able to get to market quicker. Unnecessary testing on human
and animal subjects is avoided. The cost of bringing a generic drug to market is
reduced, thus enabling prices to be reduced, which in turn makes the product more
accessible to the public. In the United States, 9 out of 10 prescriptions lled are for
generic drugs. The specic criteria for accepting generic copy submissions dier
slightly between Europe and the US.
8.10.1 EU Regulations
The authorisation of generic medicinal products is covered by Article 10 of the
Human Medicines Directive 2001/83/EC and Article 18 of the Veterinary Medicines
Regulation (EU) 2019/6. A generic drug is dened as a medicinal product that has:
● the same qualitative and quantitative composition in active substances as the ref-
erence product and
182 8 Variations to the Drug Authorisation Process
● the same pharmaceutical form as the reference medicinal product,
and whose bioequivalence with the reference medicinal product has been demon-
strated by appropriate bioavailability studies.
The dierent salts, esters, ethers, isomers, mixtures of isomers, complexes
or derivatives of an active substance shall be considered to be the same active
substance, unless they dier signicantly in properties with regard to safety and/or
ecacy, in which case additional safety and ecacy data are required. The ‘same
qualitative and quantitative composition’ only applies to the active ingredients.
Dierence in excipients will be accepted unless there is concern that they may
substantially alter the safety or ecacy. ‘Same pharmaceutical form’ must take into
account both the form in which it is presented and the form in which it is adminis-
tered. Various immediate-release oral forms, which would include tablets, capsules,
oral solutions, and suspensions, shall be considered the same pharmaceutical form
for this purpose. Although not falling with the denition of a generic drug, an
applicant may introduce new therapeutic uses, strengths, or pharmaceutical forms
as part of a hybrid submission, provided the changes from the reference product are
supported by appropriate preclinicaland clinical data, and residue testing in the case
of veterinary products. Similarly, pre-clinical and clinical data may be submitted to
bridge the safety and ecacy gaps in the case of similar biological products, which
may not be identical due to dierent raw materials or manufacturing processes, or
generic drugs where bioequivalence could not be established. Applications may be
submitted to the EMA if the reference product was centrally approved. Otherwise,
applications must be submitted to Member States for authorisation via either the
Decentralised or Mutual Recognition procedures. A member state may authorise a
generic drug even if the reference drug was never authorised in that state.
8.10.2 US Regulations
Requests for approval of generic drugs in the US may be submitted as an Abbrevi-
ated New Drug Application (ANDA) to CDERs Oce of Generic Drugs (OGD) or
Abbreviated New Animal Drug Application (ANADA) via the Centre for Veterinary
Medicine. Such submissions rely on the approved application of another drug with
the same active ingredient to establish safety and ecacy. The criteria under which
an abbreviated submission can be made are more restrictive than the equivalent reg-
ulations in Europe. The generic drug should normally be identical to an approved
drug in terms of active ingredient(s), dosage form, strength, route of administration,
and conditions of use. However, the applicant may petition the FDA for permission
to submit an abbreviated application for a drug product that is not identical to a
listed drug in route of administration, dosage form, and strength, or in which a sin-
gle active ingredient in a listed combination drug is substituted by another similarly
acting ingredient. New indications for use or dierent salts, esters, ethers, isomers,
mixtures of isomers, complexes or derivatives of an active substance, or other mod-
ications supported by clinical safety and ecacy studies may only be submitted as
NDA’s or NADA’s.
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8.11 Biosimilars 183
8.11 Biosimilars
The majority of drugs on the market are relatively low molecular mass, organic
molecules, generally manufactured via direct chemical synthesis. However, a
signicant and growing minority of approved drugs are far larger and more
complex and are derived from biological source material. These include traditional
biological products such as blood products, protein hormones, and vaccines,
along with the more modern ‘biopharmaceuticals’, which incorporate therapeutic
proteins produced by genetic engineering as well as gene therapy-based products.
Many protein-based biopharmaceuticals in particular command very substantial
market values and the majority of such biopharmaceutical blockbusters have lost
or will soon loose patent protection (Table 8.3).
Many biopharmaceuticals, therefore, represent attractive targets for generics
manufacturers. However, their mode of biosynthesis, as well as their structural
complexity (Table 8.4) renders it all but technically impossible to generate a product
guaranteed to be identical to the original product. In most instances, it is however
technically possible to develop a copy that is very substantially similar to the original
Table 8.3 The 10 top-selling biopharmaceutical products in 2020.
Ranking Product
Sales
value
($ billions)
Year
first
approved Company Patent expiry
1 Humira (adalimumab) 20.4 2002 AbbVie &
Eisai
2016 (US)
2018 (EU)
2Keytruda
(pembrolizumab)
14.4 2014 Merck 2028
3 Eylea (aibercept) 8.4 2011 Regeneron,
Bayer
2020 (EU)
2021 (US)
4 Stelara (ustekinumab) 7.9 2009 J&J 2023 (US)
2024 (EU)
5 Opdivo (nivolumab) 7.9 2014 BMS, Ono 2027 (US)
2026 (EU)
6 Enbrel (Etanercept) 6.4 1998 Amgen 2015 (EU)
2028 (US)
7 Prevnar 13
(Pneumococcal
13-valent Conjugate
Vaccine)
6.0 2010 Pzer 2026
8 Avastin (bevacizumab) 5.3 2004 Roche 2017 (US)
2019 (EU)
9 Trulicity (Dulaglutide) 5.0 2014 Eli Lilly 2026
10 Ocrevus (Ocrelizumab) 4.6 2017 Roche 2028
184 8 Variations to the Drug Authorisation Process
Table 8.4 Traditional “fine-chemical”-based pharmaceutical products versus
biopharmaceuticals: some comparative properties.
Property ‘Traditional’ product Biopharmaceutical
Mass Often 0.1–5.0 kDa range 5–150 kDa range
Structure Precisely known Complex and can be
heterogeneous if carrying a
post-translational modication
Synthesis Chemical, often straightforward Biological, complex
Purication Often straightforward Usually complex
Analysis Often straightforward Usually complex
Immunogenicity Often low Potentially high
(‘reference’) product, such that no clinically meaningful dierences distinguish
them. Such copies are termed ‘biosimilars’.
From a regulatory standpoint, it is evident that biosimilar approval via the
then-existing generics legislation would be inappropriate, yet their consideration
under regulatory pathways applied to genuinely new molecular entities would be
over-kill. The development of an approval pathway for such products initially pre-
cipitated one of the more complex and controversial debates within the regulatory
sciences, although globally there is now growing acceptance of such products and
their associated approval pathways.
8.11.1 EU Regulations
Globally the EU has led the way in terms of developing and implementing a regula-
tory structure facilitating the evaluation and approval of biosimilar products. Many
world regions have subsequently introduced biosimilar regulatory pathways largely
based upon the EU model. European biosimilar legislative provision is provided by
directive 2001/83/EC, as amended (2004/27/EC).
With the help of its biosimilar medicinal products working party, the EMA
has published a number of guidelines to assist applicants in the development of
biosimilar products. The guidelines (Table 8.5) are available via the EMA website.
They include an over-arching guideline initially introduced in October 2005,
which focuses upon the principles underlining the approvals process as well as the
approval pathway in overview. Two general guideline documents (one focusing
upon quality and the other upon clinical and non-clinical aspects) were introduced
in 2006, and a range of product-specic biosimilar guidelines have been introduced
over the intervening years. Moreover, several guidelines have or are in the process
of being updated in light of regulatory experience, and additional product-specic
guidelines are being developed.
The EU biosimilar regulations and guidelines necessitate the generation of
comparative data between the proposed new biosimilar product and the reference
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