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6.5 Submission and Review Process in the US 135
synthesis, while biological products describe those whose active substance is
synthesized by/extracted from biological sources. Scientically, biological products
are often (somewhat articially) categorized as ‘native’ biological products and
‘biotechnological’ products/biopharmaceuticals. Native products refer to those
produced naturally by some biological system (e.g. products extracted from blood
or some other tissue, or e.g. some antibiotics produced naturally by microorgan-
isms). Biotech products /biopharmaceuticals generally refer to products that are
engineered in some way/produced in an engineered biological system. A primary
example of the latter would be therapeutic proteins produced via recombinant DNA
technology (genetic engineering).
While it might be intuitive to assume that all chemically synthesized drugs are
assessed by CDER and all biologically synthesized drugs are assessed by CBER, it is
not quite so clear-cut in practice. Since 2003 regulatoryoversight of certain biological
products (primarily most proteins) has been transferred from CBER to CDER, as
outlined previously in Table 2.1.
Marketing applications for chemical-based drugs aresubmitted to the FDA as new
drug applications (NDAs), and the vast majority of NDAs are assessed by CDER
(historically, CBER has regulatory jurisdiction over some NDA products). Biological
applications, assessed by CDER or CBER as appropriate (Table 2.1), are submitted
to the FDA as a biologics license application (BLA). In both cases, the review cen-
tres upon drug safety, ecacy, and quality, and the fee for a full application for an
original new drug is in excess of US$ 3 million.
A designated project manager is used to coordinate a review team and act as a pri-
mary point of contact with the applicant. Once received, relevant sections of the
dossier are distributed to the review team and a preliminary technical screening
is performed to check that the submission (including fees) is complete and that a
worthwhile evaluation is possible. If deciencies are found, a refusal to le letter
must be sent to the applicant within 60 days, detailing the reasons why the sub-
mission is not acceptable. Otherwise, the application is led and the formal review
process begins. A ow chart outlining an NDA review is shown in Figure 6.17.
The review is conducted by a team of technical specialists drawn from dierent
oces within the centres. They examine the dossier in great detail, which may
involve a reanalysis or an extension of the analyses performed by the applicant.
Physicians almost always conduct the medical review and are responsible for
evaluating the clinical sections of the submission. As this tends to be crucial
to the assessment, they usually play a lead role in formulating an overall opin-
ion of the product in terms of safety, ecacy, and benet-to-risk ratio. Other
reviewers such as chemists, statisticians, pharmacologists, biopharmaceutic sci-
entists, and microbiologists (for anti-infective drugs) evaluate elements of the
dossier specic to their areas of expertise. During the course of the review, the
FDA will inform the applicant of easily correctable deciencies. The applicant
can submit an amendment to rectify such deciencies immediately and thus
allow the review to proceed smoothly. A conference call between the applicant
and the FDA may also be held for the purpose of discussing the overall progress
of the review.
136 6 Marketing Authorisation
Applicant (drug sponsor)
NDA
Application
fileable?
Review by CDER
Medical Biopharmaceutical
Statistical
Microbiology
Meetings with
sponsor
Pharmacology
Chemistry
Advisory
committee
meeting
Labeling
review
acceptable?
(1)
Inspection
of sites
acceptable?
(2)
Reviews
complete and
acceptable?
Refuse to file -
letter issued
Sponsor revises
Additional Info or revisions
requested or submitted
(amendment)
Pending
satisfactory
results
No
Yes
No
No
No
Yes
Yes
Yes
(1) Labeling in this context means
offical instructions for use
(2) Manufacturing sites and sites where
significant clinical trials are performed
NDA action
Figure 6.17 NDA review process.
When they have completed their evaluations, the primary review team prepares
reports that are then checked by their respective supervising ocers. Parallel to
the review, the project manager will ensure that any necessary GMP inspections
of manufacturing facilities or testing of drug samples is completed by the relevant
FDA oces. Finally, the project manager must coordinate the preparation of the
recommendation resulting from the review process and the appropriate action
letter, which will be used to ocially communicate the outcome. These are then
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6.5 Submission and Review Process in the US 137
passed to the appropriate director for nal review and sign-o of the action letter.
In some cases, the Director may decide to obtain a second opinion from an Advi-
sory Committee, made up of experts from outside the agency. A review by an
Advisory Committee will involve public hearings where the applicants can present
theircaseastowhythedrugshouldbeapproved.
An action letter must be issued within 180 days of the start of the review unless an
extension has been agreed with the applicant. If the submission is fully acceptable
an Approval Letter is issued. However, if there are problems remaining, the appli-
cant will receive a Not Approvable Letter (major problems), or an Approvable Letter
(minor problems) in the case of an NDA and a Complete Response Letter in the
case of a BLA. These summarise the deciencies that exist and either outline what
steps need to be taken to address the issues or explain why the application cannot
be approved. A negative action letter will usually trigger an end-of-review meeting
between the FDA and the applicant. This allows the applicant and FDA to discuss
and agree on what needs to be done to approve the application. Frequently, these
may just focus on agreeing to the nal text of the labeling or other promotional mate-
rial. A summary basis of approval (SBC) document serves a similar purpose to the
EPAR. It can be prepared by either the applicant or theFDAand contains a summary
of the safety and ecacy data on which the application was approved. A summary
of the application reviews undertaken by the FDA during its evaluation of a product
is also published by the FDA (Box 6.2).
Box 6.2 Nexviazyme, BLA Approval
Nexviazyme (avalglucosidase alfa-ngpt) is a therapeutic enzyme used to
treat a rare inherited condition known as Pompe disease. The drug sponsor
(Genzyme corp.) submitted a BLA to the FDA on 18 September 2020. The appli-
cation was assessed by CDER and the BLA was approved on 6 August 2021.
Upon its approval, an entry for Nexviazyme was included on the drugs@fda
(FDA-approved drugs) portal. The entry includes a copy of the approval letter,
the approved label/package insert, and a summary of the various reviews of
the application undertaken, which ultimately supported the approval decision.
The reviews listed include:
● Product quality review.
● Integrated review.
● Proprietary name review.
● Other reviews.
● Risk assessment and risk mitigation review.
Although redacted in part, the reviews provide an insight into the information
provided in the application and the conclusions drawn by the reviewers. Similar
entries are published for other FDA-approved drugs.
138 6 Marketing Authorisation
6.6 Chapter Review
This chapter examined the content and format of the marketingauthorisation appli-
cation as dened in the CTD. This is a harmonised format, agreed through the ICH
process, which divides submissions into ve modules, consisting of region-specic,
summary, quality, nonclinical and clinical sections. The chapter then looked at the
submission and review processes that exist in the EU and US. European authori-
sations may be granted using either a centralised community procedure, in which
the EMA is responsible for conducting the scientic evaluation or via national
procedures, in which the Competent Authority of a reference Member State takes a
lead role in evaluating the application. Applications to bring a new drug for human
use on the market in the US are accepted and considered via the NDA or BLA route.
6.7 Further Reading
ICH Guidelines
Common Technical Document (CTD), M4, M4Q, M4S, M4E
Electronic Common Technical Document (eCTD) specications, M8
www.ich.org
European Regulations and Guidance
Consolidated Human Medicines Directive 2001/83/EC, Title III
Consolidated Regulation (EC) No. 726/2004, Title II, Chapter 1
The Rules Governing Medicinal Products in the European Union, Volume 2, Notice to
Applicants, Medicinal Products for Human Use
https://ec.europa.eu/health/documents/eudralex_en
US Code of Federal Regulations and Guidance (https:// www.ecfr.gov)
21 CFR Part 314, Subparts A, B, D, E & G
21 CFR Part 601, Subparts A & C
CDER Handbook
www.fda.gov
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139
7
Authorisation of Veterinary Medicines
7.1 Chapter Introduction
The previous chapters examined the process for development and authorisation of
a drug product containing a new active ingredient for human use. This represents
the most arduous path to market for any medicinal product. This chapter proceeds
to examine the process of bringing a veterinary medicinal product to market. While
the process shares most of the principles that apply to human drugs, there are some
additional features that are unique to veterinary products. These include methods
of use and the requirement to evaluate withdrawal periods and maximum residue
limits (MRLs) in food-producing species.
7.2 Overview of Development Process for Veterinary
Medicines
The process of developing and bringing to market veterinary medicines is fun-
damentally the same as that for human medicines, but there are some important
dierences.
The fact that animals are the target species means that some of the ethical issues
associated with the development of human medicines do not arise or are not as
complex. At the outset, there is easy access to animal tissues for in vitro investi-
gations. Since all safety and ecacy trials are conducted in animals, the developer
does not have to face the challenges of subject enrolment associated with human
trials. The demonstration of ecacy in animals may also be easier. Studies can be
conducted under controlled conditions, which avoid the compounding inuences
of diet or lifestyle that may be associated with human trials. The range of condi-
tions of general interest to veterinary medicine tends to be narrower. The most com-
mon veterinary medicines are targeted at preventing or controlling infection and are
dominated by vaccines, antibiotics, and anti-parasitic drugs. It is generally easier to
establish the ecacy of such drugs where a dened eect is sought, in contrast to
many human conditions where only subtle responses may be experienced. Develop-
ment of drug delivery systems may not require the same level of complexity as for
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.
140 7 Authorisation of Veterinary Medicines
human medicines. Many target parasites are located either externally or in the gut,
while injection is an acceptable method of administration for vaccines or antibiotics.
Each target animal species will have to be individually investigated, as uniform
responses may not be obtained among species. The developer must also address the
concern that residues of chemical drugs in food-producing animals could pose a risk
to human health. Thus, the metabolism and excretion of the drug must be thor-
oughly investigated with a view to establishing appropriate MRLs and withdrawal
periods that will assure the safety of food products derived from treated animals.
A further aspect that may add to the development work relates to the method of
administration. In addition to the standard methods of administration associated
with human medicines, veterinary medicines maybe introduced toanimals through
medicated feeds. Such practices have been most commonly associated with the use
of antibiotics or other substances to enhance animal performance under intensive
farming systems. The use of medicated feeds is restricted in the EU, where Regula-
tion (EU) 2019/4 bans the use of antimicrobials in medicated feed for prophylaxis
and growth promotion, restricts veterinary prescriptions with antimicrobials, estab-
lishes harmonised limits for antimicrobials in ordinary feed, sets harmonised stan-
dards for manufacturing safe medicated feed and creates a legal framework for safe
manufacturing and distribution of medicated feed for pets.
In the US, medicated feeds are still relatively commonplace. Thus, the developer
may have to consider the stability and appropriate labelling of the drug when com-
pounded into medicated feeds.
7.2.1 Pre-clinical Studies
The preclinical phase of development of veterinary medical products follows a
similar pattern to that of human drugs. The developer will focus on establishing the
pharmaceutical and toxicological properties of the drug and generating data on the
chemistry/identity, manufacture, control and stability of the product. Animal drugs,
in general, have a greater probability of release to the environment than human
drugs, through either animalexcreta or directly into water in the case of sh farming.
Thus, the developer is more likely to have to conduct specic ecotoxicology studies
to assess the impact of the drug on the environment. In the case of chemical drugs
intended for use in food-producing species, the non-clinical development must
include the establishment and validation of appropriate analytical methods that
enable detection and quantication of residues of the drug or its metabolites in food
products such as meat, milk, eggs or honey. Unlike human medicines, signicant
amounts of basic ecacy data may be generated in the pre-clinical phase of drug
development by conducting studies in target species maintained under laboratory
conditions. Immunological products will also require some specic types of study,
particularly when prepared from live or modied organisms that could pose a threat
to the wider environment. These would include investigations of the excretion of
organisms from treated animals, the potential for re-emergence of virulence on
passage through the host animals, and possible adverse impacts on non-vaccinated
animals or other species. Generally, trials must be conducted in each target species
under controlled bio-secure laboratory conditions before eld trials can commence.
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7.2 Overview of Development Process for Veterinary Medicines 141
As with human pharmaceuticals, all safety studies must be conducted in accor-
dance with the principles of Good Laboratory Practice. Similar to the ICH, the
Veterinary International Conference on Harmonisation (VICH) has developed
agreed guidelines on the types of tests and other considerations that need to be
addressed during the development and evaluation of veterinary medicines. The list
of VICH guideline topics is shown in Table 7.1.
According to US regulations, drugs shipped to test facilities for nonclinical inves-
tigations must contain the following label warning:
‘Caution. Contains a new animal drug for investigational use only in
laboratory research animals or for tests in vitro. Not for use in humans’
(see CFR part 511 – new animal drugs for investigational use).
7.2.2 Clinical Trials
Clinical trials must be conducted to establish safety in each target animal species,
which in the majority of cases will include food-producing species. Although the
same type of animals may be involved in both pre-clinical and clinical trials, clear
distinction can be drawn between each type of study. Pre-clinical studies are only
conducted in animals that are kept for the purposes of laboratory research and
that are usually maintained in a very controlled environment. Clinical trials on
the other hand are conducted in animals that are representative of the normal
conditions (eld conditions) and purposes for which they are maintained. The
process of initiating animal clinical trials is not as arduous as that for human trials.
The main concerns relate to ensuring that food from trial animals will not pose
a risk to human health and that the drug will not have an adverse eect on the
environment. Of course, all trials should be conducted so as to minimise suering
and adverse impacts on animal welfare, but there is not the same level of ethical
or safety concerns as applies to human trials. Studies may follow a similar pattern
to human trials in that safety and ecacy may be established initially in clearly
dened groups of animals. Investigations may then be expanded to explore the
impact of dierent eld conditions that could be encountered, such as climate,
diet or animal husbandry practices. In food-producing species, particular attention
must be given to residue depletion and elimination studies. The potential to
develop resistance must be investigated in the case of anti-biotic and anti-parasitic
drugs.
7.2.3 Good Clinical Practices
VICH guideline GL9 sets out the principles of Good Clinical Practices for clinical
trials of veterinary medicines. The guideline has not been incorporated into specic
regulations, but it should be followed as it provides assurance to both the regulatory
authorities and the public at large as to the following:
● That the data and reported results are complete, correct and accurate,
● That the welfare of the study animals and the safety of the study personnel
involved in the study are ensured and
● That the environment and the human and animal food chains are protected.
142 7 Authorisation of Veterinary Medicines
Tabl e 7. 1 Topics addressed by VICH guidelines.
Document no. Topic Title of guidelines
GL1 Validation denitions Validation of analytical procedures:
denition and terminology
GL2 Validation methodology Validation of analytical procedures:
methodology
GL3 Stability 1 Stability testing of new drug substances
and products
GL4 Stability 2 Stability testing for new dosage forms
GL5 Stability 3 Stability testing: photostability testing of
new drug substances and products
GL6 Ecotox Phase I Environmental impact assessments (EIAs)
for veterinary medicinal product (VMPs)
Phase 1
GL7 Anthelmintics general Ecacy of anthelmintics: general
requirements
GL8 Stability premixes Stability testing for medicated premixes
GL9 GCP Good Clinical Practices
GL10 Impurities substances Impurities in new veterinary drug
substances
GL11 Impurities products Impurities in new veterinary medicinal
products
GL 12 Anthelmintics bovine Ecacy of anthelmintics: specic
recommendations for bovines
GL13 Anthelmintics ovine Ecacy of anthelmintics: specic
recommendations for ovines
GL14 Anthelmintics caprine Ecacy of anthelmintics: specic
recommendations for caprines
GL15 Anthelmintics equine Ecacy of anthelmintics: specic
recommendations for equines
GL16 Anthelmintics porcine Ecacy of anthelmintics: specic
recommendations for porcines
GL17 Stability:
Biotechnologicals/biologicals
Stability testing of new
biotechnological/biological products
GL18 Impurities: Residual Solvents Impurities: residual solvents in new
veterinary medicinal products, active
substances and excipients
GL19 Anthelmintics canine Ecacy of anthelmintics: specic
recommendations for canine
GL20 Anthelmintics feline Ecacy of anthelmintics: specic
recommendations for feline
GL21 Anthelmintics poultry Ecacy of anthelmintics: specic
recommendations for poultry
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7.2 Overview of Development Process for Veterinary Medicines 143
Tabl e 7. 1 (Continued)
Document no. Topic Title of guidelines
GL22 Safety reproduction Studies to evaluate the safety of residues of
veterinary drug in human food:
reproduction studies
GL23 Safety genotoxicity Studies to evaluate the safety of residues of
veterinary drug in human food:
genotoxicity testing
GL24 Pharmacovigilance Pharmacovigilance of veterinary medicinal
products: management of Adverse Event
Reports (AERs)
GL25 Biologicals Testing of residual formaldehyde
GL26 Biologicals Testing of residual moisture
GL27 Antimicrobial resistance Guidance on pre-approval information for
registration of new veterinary medicinal
products for food-producing animals with
respect to antimicrobial resistance
GL28 Safety carcinogenicity Studies to evaluate the safety of residues of
veterinary drug in human food:
carcinogenicity testing
GL29 Pharmacovigilance PSU Pharmacovigilance of Veterinary Medicinal
Products: Management of Periodic
Summary Update Reports (PSUs)
GL30 Pharmacovigilance list of
terms
Pharmacovigilance of Veterinary Medicinal
Products: controlled list of terms
GL31 Safety: Repeat-dose toxicity
test
Studies to evaluate the safety of residues of
veterinary drugs in human food:
Repeat-dose toxicity testing
GL32 Safety: Developmental
toxicity test
Studies to evaluate the safety of residues of
veterinary drugs in human food:
Developmental toxicity testing
GL33 Safety: General approach to
testing
Studies to evaluate the safety of residues of
veterinary drugs in human food: General
approach to testing
GL34 Biologicals: Mycoplasma Test for the detection of Mycoplasma
contamination
GL35 Pharmacovigilance: ESTD Pharmacovigilance: Electronic Standards
for Transfer of Data
GL36 Safety: Microbiological ADI Studies to evaluate the safety of residues of
veterinary drugs in human food: General
Approach to establish a microbiological
ADI
GL37 Safety: Repeat dose chronic
toxicity
Studies to evaluate the safety of residues of
veterinary drugs in human food:
Repeat-dose Chronic Toxicity Testing
(Continued)
144 7 Authorisation of Veterinary Medicines
Tabl e 7. 1 (Continued)
Document no. Topic Title of guidelines
GL38 Ecotoxicity Phase II Environmental Impact Assessment (EIAs)
for Veterinary Medicinal Products
(VMPs) – Phase II
GL39 Quality: Specications Test Procedures and Acceptance Criteria
for new Veterinary Drug Substances and
New medicinal Products: Chemical
Substances
GL40 Quality: Specications Test Procedures and Acceptance Criteria
for new Biotechnological/Biological
Veterinary Medicinal Products
GL41 TAS: Reversion to virulence Examination of live Veterinary Vaccines in
Target Animals for Absence of Reversion to
Virulence
GL42 Pharmacovigilance: Data
elements
Pharmacovigilance: Data Elements for
Submission of Adverse Events Reports
GL43 TAS: Pharmaceuticals Target Animal Safety for Pharmaceuticals
GL44 TAS: Biologicals Target Animal Safety for Veterinary live
and inactivated Vaccines
GL45 Quality: Bracketing and
Matrixing
Bracketing and Matrixing Designs for
Stability Testing of new Veterinary Drug
Substances and Medicinal Products
GL46 MRK: Nature of residues Studies to evaluate the Metabolism and
Residue Kinetics of Veterinary Drugs in
Food-producing Animals: Metabolism
Study to determine the Quantity and
Identify the Nature of Residues
GL47 MRK: Comparative
metabolism studies
Studies to evaluate the Metabolism and
Residue Kinetics of Veterinary Drugs in
Food-producing Animals: Comparative
Metabolism Studies in Laboratory Animals
GL48 MRK: Marker residue
depletion studies
Studies to evaluate the Metabolism and
Residue Kinetics of Veterinary Drugs in
Food-producing Animals: Marker Residue
Depletion Studies to establish Product
Withdrawal Periods
GL49 MRK: Method used in
Residue Depletion Studies
Guidelines for the Validation of Analytical
Methods used in Residue Depletion Studies
GL50 Biologicals: TABST Harmonisation of criteria to waive target
animal batch safety testing (TABST) for
inactivated vaccines for veterinary use
GL51 Quality: Stability data Statistical evaluation of stability data
GL52 Bioequivalence: Blood level Blood Level Bioequivalence Study
GL53 Electronic le format Electronic exchange of documents: File
format requirements
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