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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5608_Библиотеки_им_академика_М_И_Перельмана.pdf
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K. Arch-Douglas et al.
Applications for clinical trials are led under Investigational New Drug applications (IND). Typically, a single IND is opened per product and as clinical development progresses, IND amendments are led with new information (e.g., new clinical
protocols, clinical and nonclinical study reports, CMC [Chemistry, Manufacturing
and Control] changes).
Biologics and Vaccine license applications are submitted as Biologics License
Applications (BLA). License applications for over-the-counter and prescription
drugs are submitted as New Drug Applications (NDA).
16.1.1.2 European Union
The European Union (EU) is organized quite differently. The European Commission
(EC) proposes new legislation and ensures that EU law is correctly applied by member states. EU legislation concerning the regulation of medicines is adopted by the
European Parliament and the Council of the European Union. The European
Commission takes binding decisions on the centralized authorization of medicines
based on European Medicines Agency (EMA) scientic assessments of marketing
authorization applications (MAA), ensuring that medicines comply with high quality, safety, and efcacy standards.
The European Medicines Agency has seven scientic committees and a number
of working parties and related groups that conduct the scientic work:
• Committee for Medicinal Products for Human Use (CHMP)
• Pharmacovigilance Risk Assessment Committee (PRAC)
• Committee for Veterinary Medicinal Products (CVMP)
• Committee for Orphan Medicinal Products (COMP)
• Committee on Herbal Medicinal Products (HMPC)
• Committee for Advanced Therapies (CAT)
• Paediatric Committee (PDCO)
• Working parties and other groups
Applications for clinical trials are led as a Clinical Trial Application (CTA)
and quality information is provided in the Investigational Medicinal Product
Dossier (IMPD) component of the CTA.Typically, a new CTA is led for each
clinical study. The CTA review process was historically governed by individual
National Competent Authorities; however, an optional centralized Voluntary
Harmonized Procedure (VHP) is currently in place. Also, since January 2022, the
Clinical Trials Regulation (CTR) came into application, harmonizing the submission, assessment, and supervision processes for clinical trials in the European
Union (EU).
License applications for biologics, drugs, and vaccines are submitted as a
Marketing Authorization Application (MAA).
16 Overview ofComplexities ofGlobal CMC Regulatory Affairs
461
16.1.2 Global Markets
There are numerous other markets and associated HAs in which CMC content and
license review will likely differ around the globe. A few rest-of-world market/HA
examples are:
• China: NMPA (National Medical Products Administration)
• Japan: PMDA (Pharmaceuticals and Medical Devices Agency)
• Canada: HC (Health Canada)
• Australia: TGA (Therapeutic Goods Administration)
• Korea: MFDS (Ministry of Food and Drug Safety)
• India: MHFW (Ministry of Health and Family Welfare)
• Hong Kong Department of Health
• Taiwan: MHW (Ministry of Health and Welfare)
• Brazil: ANVISA (Agencia Nacional de Vigilancia Sanitaria—Brazilian Health
Regulatory Agency)
• Mexico Ministry of Health
• Russia Ministry of Health
• Israel Ministry of Health
• Other Latin America Countries (Argentina, Peru, etc.)
There are several key aspects about vaccines that greatly inuence regulatory
behaviors. First, vaccines are not “drugs”; they are vehicles to elicit a response (e.g.,
antibodies) to combat disease. Prophylactic vaccines aim to prevent disease and are
given to healthy subjects while therapeutic vaccines aim to treat disease and are
given to patients. Next, the concept of a “well-characterized product” does not apply
to vaccines (i.e., “the process is the product”) and each vaccine manufacturing process is unique.
16.1.3 Examples ofCore Differences inRegulatory
Requirements Globally
In the United States alone, the Code of Federal Regulations (CFRs) have different
regulations for NDAs, which fall under 21 CFR Part 314, and BLAs, which fall
under 21 CFR Part 600 (for Biologics Products: General), 21 CFR Part 601
(Licensing), 21 CFR Part 610 (General Biologics Products Standards), 21 CFR
601.2(a) Specied biological products, and Biosimilar and interchangeable products subject to licensure under section 351(k) of the Public Health Service (PHS)
Act (42 U.S.C. 262(k)). There are also a number of FDA-issued guidance documents for small molecules, biologics, vaccines, and medical devices.
As new technology and understanding develops with these products, the regulations sometimes change or are updated. One recent example is the removal of the
General Safety Test (GST) from the US CFR.This test was designed to test for
462
extraneous toxic contaminants on each product lot intended for human use. The test
required one-week observations for general health and weight following injection of
specied volumes of product batches into guinea pigs and mice. This test was previously listed in 21 CFR 610.11 but was removed from the CFR in 2015. FDA stated
in the Final Rule for removal that “FDA is nalizing this action because the existing
codied GST regulations are duplicative of requirements that are also specied in
BLAs or are no longer necessary or appropriate to help ensure the safety, purity, and
potency of licensed biological products. FDA is taking this action as part of its retrospective review of its regulations to promote improvement and innovation, in
response to the Executive order.”
Similarly, the Abnormal Toxicity Test (ATT) was previously listed in the Ph. Eur.
2.6.9 and was required for testing Immunosera and Vaccines for Human Use was
also previously used for testing general health of mice and guinea pigs 1 week after
injection. This test was removed from Ph. Eur. in 2017 as part of European
Commission Directive of Replacement, Reduction and Renement of animal testing (3Rs) per Directive 2010/63/EU on the protection of animals used for scientic
purposes.
It should be noted that while the GST and the ATT are no longer required by the
FDA and EMA, respectively, regulatory authorities in other commercial markets
still require these tests to be performed.
In recent years, a hot topic for CDER-regulated Biologics was concerning the
inclusion of microbial control information in the NDAs and BLAs, which was
driven by the formation of CDER’s Ofce of Pharmaceutical Quality (OPQ) and
increased involvement in dossier review by OPQ’s Division of Microbiology
Assessment.
K. Arch-Douglas et al.
16.2 Complexities inNavigating Global Market Drug
Development andManaging Multiple Market Dossiers
Even though the major markets (e.g., the United States, EU, Japan, Canada,
Australia) follow the ICH CTD format for CMC information, each market has its
own set of regulations and guidance and may have their own compendial requirements for testing.
Even within these markets, the regulatory requirements are different for small
molecules, biologics, and vaccines. For example, most major markets require lot
release testing of vaccine lots before they are allowed into commercial distribution
in that market. All lots of commercial vaccines, in both the United States (21 CFR
610.2) and EU (Directive 2001/83/EC amendment Directive 2004/27/EC (7, 8)),
require lot-by-lot release and testing by government laboratories prior to commercial distribution. This lot release testing consists of the sponsor sending samples of
each lot intended for commercial distribution to each country’s testing lab for
16 Overview ofComplexities ofGlobal CMC Regulatory Affairs
463
testing against the company’s Certicate of Analysis (COAs) and releasing the lot.
This lot release testing is no longer a requirement for most biologics and small
molecules.
Several other markets also require in-country testing of products before they can
be commercially approved (for example: Australia, Canada, China, Russia, Saudi
Arabia). In addition, due to numerous climates and supply chain requirements, various shipping validation requirements would need to be met (e.g., cycling studies to
support excursions during transportation).
In China, the Drug Registration Regulation became effective in July 2020. A new
guideline on Manufacturing and Testing Procedures (MTP) and JS Specication
templates became effective in July 2021. Drug Master Files (DMFs) or Technical
Documents are required for excipients and container closures. In-country testing is
a requirement for Drug Substance and Drug Product for biologic products and vaccines at commercial stage and vaccines at the clinical stage, while there is no formal
process for transfer of test methods to the National Institutes for Food and Drug
Control. This highlights the evolving landscape of regulatory requirements for commercial registrations in China.
Some global markets are moving toward a Reliance Model pathway (Eurasian
Economic Union [EAEU], Balkans, Egypt) to reduce initial application approval
timelines. However, divergence between the World Health Organization (WHO),
national regulatory authorities (NRA), and industry on the denition and scope of
“product sameness” is a challenge. Most global emerging markets now follow the
ICH CTD template format for chemistry, manufacturing, and control (CMC) information but many markets require specic detailed regional documentation, which
make it difcult to maintain a core dossier type of approach for CMC content. These
regional requirements vary from country to country and include items such as:
• Country-specic normative documents
• Local application forms
• Canada specic Certied Product Information Document (CDIP)
• Certied Product Details (CPDs)
• Manufacturing and Testing Procedures (MTP)
• GMP (Good Manufacturing Practice) documents such as site/plant master les
• Country-specic declarations for CMC materials
• Ancillary documents such as stability chromatograms, cell bank COAs, certi-
cates of source of raw materials
For some markets, such as China, Russia, and South Korea, these countryspecic CMC documentation requirements require a signicant amount of time and
resources to prepare the documentation. Additionally, some countries, such as
Turkey, require GMP pre-clearance before the commercial application for the drug
or vaccine can be submitted. This entails either an onsite or paper inspection of each
manufacturing site by Turkey’s Ministry of Health where a GMP certicate is issued
for each site following pre-clearance.
Additionally, each market has its own targeted timelines for initial review of
submissions. For example, in the United States, a BLA review period is 12months
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for standard review and 8months for BLAs that receive priority review designation
from FDA.Initial applications in various global markets have taken more than 2
years to obtain commercial approval. Subsequent initial applications to global markets often occur over the next several years. Any changes to manufacturing processes, shelf-life, test procedures, etc. during this timeframe may cause challenges
from a global supply perspective due to the amount of time it takes to obtain approvals in all markets. Many health authorities do not allow changes to be submitted
during the initial registration review period.
Timeframes to obtain approvals for post-approval CMC changes in global markets may vary from a minimum of a few months to in excess of 2 years. Management
of these changes requires close communication between regulatory affairs and commercial supply colleagues and strong oversight of global commercial inventory to
ensure that there is no stock-out of commercial inventory in each market.
K. Arch-Douglas et al.
16.3 The Role ofWHO andICH inGlobal
Drug Development
The World Health Organization (WHO) is a United Nations agency founded in 1948
to connect nations and promote health and keep the world safe and especially serve
the vulnerable. Through working with 194 Member States across 6 regions, the
WHO is a decision-making body that is responsible for collaborations with governments to ensure everyone in the world can remain healthy and for coordinating the
world’s response to health emergencies like the recent COVID-19 pandemic.
As part of the WHO’s essential global role in governance of health and disease,
there are a number of technical and regulatory guidance documents drafted by the
WHO to help unify approaches of regulation of medicinal products and vaccines. In
response to the COVID-19 pandemic, the WHO published a number of technical
guidances for the detection, prevention, and control of this virus.
The mission of the ICH “is to achieve greater harmonization worldwide to ensure
that safe, effective, and high-quality medicines are developed and registered in the
most resource-efcient manner. Harmonization is achieved through the development of ICH Guidelines via a process of scientic consensus with regulatory and
industry experts working side-by-side. Key to the success of this process is the commitment of the ICH regulators to implement the nal Guidelines” (ICH Ofcial web
site: ICH).
An example of the ICH harmonization process was the advent of the Common
Technical Document (CTD) in 2003. This conceptualized the idea of global harmonization by providing a format for the assembly of quality, safety, and efcacy information and data to be included in a pharmaceutical product dossier. Global
acceptance for dossier formatting by the manufacturer is important because it allows
a signicant ease in the burden associated with the regulatory review process by
health authorities, which allows regulatory approvals to accelerate. Often
16 Overview ofComplexities ofGlobal CMC Regulatory Affairs
465
overlooked and just as important, however, is the desire for acceptance of dossier
formatting and required information by global health authorities, as aligning global
country requirements eases the regulatory burden on the manufacturer. Encouraging
the acceptance of CTD format is important for HAs and manufactures alike, as it
benets both. The ICH has provided the CTD triangle, which is a visual representation of the structure of the CTD; this is provided in Fig.16.1.
The CTD is organized into ve modules. Module 1, consists of regional administrative information. This is not considered part of the CTD, because regional information is always country specic, so it cannot be aligned across global applications.
Examples of Module 1 documentation could be country-specic forms, cover letters, meeting requests, labeling or promotional materials, general correspondence
with the HA, among others.
Module 2, consists of summaries of the quality, pre-clinical, and clinical modules that are all the remaining modules (3, 4 and 5).
Module 3, is the CMC module. The Quality-M4Q(R1) guidance by the ICH
describes the CTD backbone structure for all quality information as it relates to
manufacturing, drug substance, and drug product.
Module 4, is the pre-clinical and nonclinical module. The Safety-M4S(R2) guidance by the ICH describes the CTD backbone structure for all safety information as
it relates to pharmacology, pharmacokinetics, and toxicology.
Fig. 16.1 CTD triangle. (Captured from www.ICH.org [3])
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Module 5, is the clinical study module. The Efcacy-M4E(R2) guidance by the
ICH describes the CTD backbone structure for all clinical pharmacology, clinical
efcacy, and clinical safety studies.
Prior to the implementation of CTD, the CMC content for investigational and
commercial submissions varied from country to country. Although the CTD format
is now accepted globally, each market has its own regulations (i.e., laws, legal
requirements) and guidance documents (i.e., regulatory agency interpretation/application of laws) that often require different submission content that results in divergence from a common technical document.
While ICH and WHO help to harmonize practices, several health authorities
throughout the world maintain their own national laws and guidelines that govern
regulatory activities. As with other medicinal products, there are numerous markets,
global and national, in which CMC content, license review, and approval timelines
will differ depending on the associated health authority. For example, some health
authorities require a lot-to-lot manufacturing-consistency clinical study to be conducted during Phase 3, additional country-specic documentation to be led, or
lot-by-lot release testing to be executed by country labs prior to distribution.
K. Arch-Douglas et al.
16.4 Complexities ofEmergency Use inaPandemic
A pandemic is dened as a global outbreak of an infectious disease. The world has
seen its share of pandemic-level events from the Bubonic plague, that killed about
30% of Europeans during the 1300s [4], to the Spanish Flu, that killed 50 million
plus people worldwide in 1918 [5]. However, no global outbreak of an infectious
disease has been more front and center in recent times than that of the COVID-19
pandemic.
On Tuesday, December 21, 2019, Chinese authorities alerted the WHO to a mysterious virus causing pneumonia-like illness in a small cluster of patients within the
city of Wuhan. Shortly after, a novel virus was identied as severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) [6]. Less than 4 months later on March 11,
2020, the WHO declared the novel SARS-CoV-2, otherwise known as Coronavirus
Disease-2019 (COVID-19), outbreak a global pandemic [7]. This declaration drove
novel technologies into the forefront of biopharmaceutical science and challenged
the traditional paradigm of vaccine development.
16.4.1 United States FDA
In the United States, Under section 564 of the Federal Food, Drug, and Cosmetic
Act (FD&C Act), when the Secretary of HHS declares that an emergency use authorization is appropriate, FDA may authorize unapproved medical products or unapproved uses of approved medical products to be used in an emergency to diagnose,
16 Overview ofComplexities ofGlobal CMC Regulatory Affairs
467
treat, or prevent serious or life-threatening diseases or conditions caused by chemical, biological, radiological and nuclear (CBRN) threat agents when certain criteria are met, including there are no adequate, approved, and available alternatives
[8]. On January 31, 2020, the Secretary of the Health and Human Services (HHS)
determined the most appropriate course of action was to do just that, and they issued
a declaration of a public health emergency related to COVID-19 and mobilized the
Operating Divisions of HHS [9].
The FDA and EMA began to collaborate with other countries to help facilitate
COVID-19 vaccine development. They rst convened on March 18, 2020, with representative experts from 17 different countries and the World Health Organization
to discuss the pre-clinical data requirements that would be needed from a manufacturer for a pandemic vaccine candidate to precede to rst-in-human clinical trials.
The FDA and EMA would also continue to convene at future dates with other global
regulators to enable sharing of clinical trial data as a means of ensuring global preparedness and streamlining vaccine development [10].
The FDA has the authority to issue an Emergency Use Authorization (EUA),
which is in accordance with section 564 of the Food, Drug, and Cosmetic Act (21
U.S.C. 360bbb-3). During the initial development of a vaccine candidate for
COVID-19, vaccine manufacturers only had the FDA guidance published in June of
2020, Development and Licensure of Vaccines to Prevent COVID-19, to use as a
source guidance document to build their regulatory strategies. In this guidance the
agency put forth their requirements for developmental vaccines to be considered for
EUA.From a clinical trial perspective, they stated that “To ensure that a widely
deployed COVID-19 vaccine is effective, the primary efcacy endpoint point estimate for a placebo-controlled efcacy trial should be at least 50%” [11], meaning
that a vaccine candidate need only show 50% effectiveness, similar to the annual
inuenza vaccine to be considered for licensure.
The FDA later released the guidance document, Emergency Use Authorization
for Vaccines to Prevent COVID-19, in May of 2021, which has since been superseded as of March 31, 2022. This guidance provides the requirements for key information that should be provided to the IND application prior to submitting an EUA
request. Providing this key information will allow the FDA to facilitate a timely
review of submission content and convene with the Vaccines and Related Biological
Products Advisory Committee (VRBPAC) [12].
In addition to the FDA guidance documents that were set forth specically to
manage the COVID-19 pandemic, the FDA also allowed the manufacturers of
COVID-19 vaccine candidates to meet more frequently either via virtual telecommunications or through brieng documents (since the country was on lockdown,
there were no face-to-face meetings) to get their questions answered for what would
be needed in a potential emergency use application.
The United States government started Operation Warp Speed that was being
overseen by HHS Secretary Alex Azar and Defense Secretary Mark Esper, which
aimed at speeding up vaccine development efforts to enable the delivery of safe and
effective vaccine doses by January of 2021. This was done by focusing on three key
phases: development, manufacturing, and distribution.
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K. Arch-Douglas et al.
This effort from the United States government and the FDA as well as open
global collaboration helped set the stage for major manufacturers like Pzer and
Moderna, during the clinical development phase, to be able to establish their developmental strategies with more certainty as everyone was operating with the same
end goal, of getting lifesaving preventative vaccines for patients.
In the book Moonshot by Pzer Inc. CEO Dr. Albert Bourla, he notes that Pzer
began testing four different vaccine candidates in Phase 1 trials in May of 2020 and
developed a clinical trial design and manufacturing infrastructure plan that would
cost upward of two billion dollars to implement. There are many ways Pzer was
able to develop a vaccine candidate in 9 months and one major reason was because
of their clever trial design strategy. Dr. Bourla notes “Traditionally, those would
have been tested sequentially, but we decided to test them in parallel– four different
vaccine candidates, each at three different dosage levels. Such an effort might take
a year under normal circumstances. We did it in a month. By late July 2020, we
were prepared for a combined Phase 2 and 3 trial in which eventually over 46,000
patients would be recruited at 153 clinical sites in six countries” (Moonshot, p.51)
[6]. Pzer received the clinical readout of their pivotal Phase 3 data on November 8;
the readout showed to be 95.6% efcacious. They then proceeded to submit their
initial EUA submission on November 20 and the U.S.FDA granted Pzer Emergency
Use Authorization on December 11, 2020.
16.4.2 European Medicines Agency (EMA)
In Europe (EU), COVID-19 pandemic has had a considerable impact on citizens,
patients, and businesses, and this posed unprecedented challenges in ensuring continuity of supplies of medicines or providing medicines against the COVID-19 virus
while ensuring that the high standards of quality, safety, and efcacy of medicines
made available to patients are maintained. In June 2020, the European Commission
(EC) announced the EU strategy (1) around COVID-19 vaccines. Taken the unprecedented crisis, the ambition was to deliver a successful vaccine within a timeframe
of 12–18months and, once a successful COVID-19 vaccine is available, to produce
high amounts of doses in order to cover global needs, without compromising the
production of other essential vaccines. To this end, the EU mobilized resources and
joined forces with global health organizations through the Access to COVID-19
Tools (ACT) Accelerator collaborative effort. As part of the effort to help protect
people everywhere and EU citizens in particular, the EC proposed an EU strategy to
accelerate the development, manufacturing, and deployment of vaccines against
COVID-19.
The strategy has three major objectives and is based on two pillars:
(a) Ensuring the quality, safety, and efcacy of vaccines
(b) Securing timely access to vaccines for Member States and their population
while leading the global solidarity effort
16 Overview ofComplexities ofGlobal CMC Regulatory Affairs
469
(c) Ensuring equitable access for all in the EU to an affordable vaccine as early as
possible
(d) Securing sufcient production of vaccines in the EU and thereby sufcient sup-
plies for its Member States
(e) Adapting the EU regulatory framework to the current urgency and making use
of existing regulatory exibility
The EMA offers applicants a pathway to a conditional marketing authorization,
whereby medicines may be granted conditional use with less comprehensive initial
clinical data when the benet of the immediate availability outweighs the inherent
risk associated with the use of the therapeutic or preventative drug. Conditional
marketing authorization may be granted by the Committee for Medicinal Products
for Human Use (CHMP) in accordance with Article 14-a of Regulation (EC) No
726/2004 [13].
EMA’s CHMP may grant a conditional marketing authorization for a medicine
if it nds that all of the following criteria are met:
• The benet–risk balance of the medicine is positive.
• It is likely that the applicant will be able to provide comprehensive data
post-authorization.
• The medicine fulls an unmet medical need.
• 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.
16.4.3 The World Health Organization
The WHO has an Emergency Use Listing Procedure (EUL), which is used as a riskbased procedure to assess unlicensed vaccines, therapeutics, and invitro diagnostics. The intention of this procedure is to expedite the availability of these products
to people that are affected by public health emergencies [14].
On November 25, 2020, the WHO released a guidance document titled
Considerations for the Assessment of COVID-19 Vaccines for Listing by WHO. This
document was to be used by Manufacturers to understand the WHO’s terms for
what they would consider a viable vaccine candidate for an EUL.Like any guidance
document, it is not a comprehensive step-by-step guide on vaccine development but
it did put forward some important considerations.
This guidance also covers CMC considerations such as characterization of the
starting material and drug substance, process controls, and process validation. The
guidance states that: “As an alternative to the traditional process validation, continuous process verication can be utilized in process validation protocols for the initial
commercial production and also for manufacturing process changes for the continual improvement throughout the remainder of the product lifecycle” [14].