Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5981_Библиотеки_им_академика_М_И_Перельмана
.pdf
is to evaluate a range of doses to establish a MED to extrapolate for human dosing. Careful
consideration for the chosen disease model is warranted as it may impact the evaluation of
‘efficacious doses’ (e.g., when the disease model overexpresses a pathogenic human gene
at supra-physiological levels).
While pharmacologic efficacy studies are typically conducted as non-GLP studies, robust
study designs that include standard procedures for evaluating critical endpoints, prospective
study protocols, and processes to capture changes or deviations to the study contemporane-
ously improve the data quality and robustness. There are no set rules on gender, age at
dosing, numbers of animals or duration of studies. A single sex may be used for efficacy,
particularly if the genetic target is sex specific. A sufficient number of animals should be
enrolled to power statistical analyses and account for animals that may die on study. The
study should be conducted for sufficient duration to show clear separation from the control
group(s). In studies where survival is included as a key efficacy endpoint, inclusion of an
earlier interim euthanasia may be warranted in order to asses s the therapeutic impact of
the GT on other disease-relevant endpoints.
In general, the age at dosing should be carefully considered to approximate the intended
clinical population. If adult patients are the intended population, then adult animals should
be used, and if pediatric patients are to be treated then neonatal or juvenile animals would be
most relevant. Where possible, endpoints should be quantitative to minimize potential for
observer bias that often occurs with qualitative assessments. If changes in cellular
morphology are a key feature, image analysis tools can be leveraged to transform the
observed changes into quantifiable data sets. Functional endpoints, such as muscle or grip
strength or neurological responses, which can be timed or scored, should include robust pro-
tocols and user traini ng to ensure reproducibility.
In summary, establishing the most appropriate designs to test the efficacy of GT products
in nonclinical models of disease inherently rely on a deep understanding of the disease itself,
the model phenotype, the vector biodistribution and transgene expression in that species, and
the intended clinical application. A clear justification for animal models and study designs
selected, including how the model approximates the human disease, and key assumptions
or aspects in which the model is deficient are critical elements of the nonclinical package
in initial regulatory submissions. Both US and European regulators clearly define these ex-
pectations in their respective guid ance documents for GTs and biologics (EMA, 2008b ;
FDA, 2013).
Pharmacodynamics and pharmacokinetics
Pharmacodynamics and minimal efficacious dose (MED)
Pharmacodynamics is an evaluation of what a therapeutic does to the body e namely the
activity of the drug. This activity is typically described in terms of a dose-dependent effect on
target cell(s). Ideally, thresholds can be established that describe the effective dose (ED) that
produces a change in, for example, 50% or 90% of the target cells (ED50 or ED90). Having a
clear understanding of the disease and what percentage of cells may need to be corrected for
efficacy in patients is helped by estimates of the ED in animal models. By establishing these
9. Preclinical development of viral vector gene therapies276
III. Specialty biologics and indications
thresholds, investigators are aided in predicting the human equivalent dose (HED) that
would be necessary to produce a positive clinical outcome.
In the pivotal IND-enabling pharmacology study, if feasible, three to five dose levels
should be evaluated so that the MED and maximal feasible/tolerable dose (MFD/MTD)
can be defined. Selection of doses utilized should ensure sufficient separation to account
for the variability in the vector titer assay. For example, if the titer values have a standard
deviation of w25%, dose levels should be separated by at least a factor that exceeds this vari-
ation to meaningfully interpret the activity. For GTs, the range of doses that can be reason-
ably tested may be limited by the total volume that can be administered via the desired
ROA as well as the final titer of the material. Dose justification and extrapolation to clinically
meaningful starting doses must be clearly defined and are a key element of a nonclinical
package to enable FIH exposure.
Pharmacokinetics e biodistribution, shedding, and persistence
Traditionally pharmacokinetic (PK) studies are performed to describe a drug’s exposure to
the body by understanding its absorption, distribution, metabolism, and excretion (ADME).
Such criteria cannot be strictly applied to GT products as they combine both a carrier (vector)
and product (transgene) (Yla-Herttuala, 2017). Historically, only distribution and excretion
(viral shedding) of vector genomes were required for GTs and formed the bulk of the PK
description in the nonclinical package. Now there is growing awareness that several factors
can impact PK, including presence of empty or partially filled viral particles (which can satu-
rate target cell receptors), preexisting antibodies, innate immune responses such as comple-
ment, host cell restriction factors, or even the disease state of the model. Importantly, the
detection and quantification of the transgene product is the most relevant metric to predict
clinical impact. Ideally, the expressed product is measured in selected tissues collected for
biodistribution (BD) analyses in nonclinical studies.
An ICH guidance issued in 2023 (S12) provides clear recommendations for characterizing
the BD of GT products (ICH, 2023). In brief, BD can be performed as either part of nonclinical
pharmacology or toxicology studies, with appropriate design of the study to address the
presence of any preexisting immunity to the vector. The studies should include sampling
of on- and off-target tissues inclusive of gonads, at various timepoints for quantitative assess-
ment of the presence of vector genomes (e.g., by PCR methods) and transgene product (e.g.,
PCR, ELISA or LCMS methods) over time. Optimally, sampling would include: (1) an early
time point for peak vector BD within first-hours postadministration, (2) a time point to cap-
ture peak transgene expression w1-month postdosing for AAV, and (3) a time point after
peak transgene to capture any long-term change e.g., w3-month postdosing. Selection of
these time points should be based on the known biology of the vector platform e.g., time
for either second strand synthesis for AAV or reverse transcription for LV, and subsequent
transgene expression profile.
In both the US and Europe, there is a clear expectation that a sensitive, quantitative, and
qualified genomic assay such as PCR is used to evaluate distribution of ve ctor genomes. The
new ICH S12 document goes further to suggest that, if appropriate, the distribution of the
transgene expression product may also be measured (ICH, 2023). Consistent with existing
Nonclinical development 277
III. Specialty biologics and indications
guidance, sampling of the following tissues/biofluid is recommended: injection site(s), go-
nads, adrenal gland, brain, spinal cord (cervical, thoracic, and lumbar), liver, kidney, lung,
heart, spleen, and blood. This panel can be expanded depending on additional consider-
ations such as vector type/tissue tropism, the expression product, ROA, disease pathophys-
iology, and animal sex and age. For example, additional tissues and biofluids can include
peripheral nerves, dorsal root ganglia, cerebrospinal fluid, vitreous fluid, draining lymph
nodes, bone marrow, or eyes and optic nerve. Gonad BD should always be assessed to
address concerns for germline transduction and potential for vertical transmission. BD
studies should be carefully designed to avoid time consuming and costly mistakes that
may necessitate a repeat study. BD reports should include tabulations of raw data; sum-
maries should identify whether there are dose or sex-specific correlations in the distribution
of the viral vector and should also rank order tissues from those with the highest to lowest
levels of vector genomes and transgene product. For vector distribution to unwanted or un-
desired tissues, such as gonads, secondary assays can be used to determine if this leads to
transgene product expressed in germ or supporting cells as well as an interpretation for the
safety risk.
Shedding of recombinant viral vectors primarily depends on the dose and ROA of the GT
product. Guidance from the US FDA and EMA is available to aid sponsors in characterizing
vector shedding (FDA, 2015b). Per guidance, testing for viral shedding is required if
humans have not been previously exposed to the product, the product has been modified
to achieve a different in vivo tropism than the parent strain, or a novel ROA is proposed,
particularly if it differs from the natural route of infection. If required, shedding is generally
evaluated in toxicology studies to i nform the potential risk for exposure to third parties or
to the environment. This risk is maximal when high doses of GT are admini stered system-
ically, and minimal when low doses are administered locally. Importantly, most shedding
studies usually report the presence of the vector genome (detected by PCR), but not neces-
sarily the presence of functional v ector (oftentimes present at much lower levels than total
vector genomes detected in excreta). Nonetheless, the evaluation of the presence of the vec-
tor genome at dif ferent timepoints postdosing will be helpful to characterize the potential
risk of viral shedding. Biological matrices to consider for viral shedding include blood,
urine, saliva, semen and feces. Other biofluids may be included, depending upon the chosen
ROA (for example in lacrimal or nasal biofluids after ocular dosing). In most n onclinical and
clinical studies where viral shedding is evaluated, the viral load tends to drop very rapidly
after administration of the GT.
Nonclinical safety evaluation
General toxicity
FIH-enabling nonclinical toxicology studies remain the cornerstone for the safety evalua-
tion of GT products and must be conducted under GLP. Some specific analyses (such as
immunogenicity assessments or protein BD) are not required to be con ducted under GLP
conditions and clear GLP exceptions can be prospectively defined in the study protocol.
9. Preclinical development of viral vector gene therapies278
III. Specialty biologics and indications
The GLP safety study aims to identify and characterize toxicities that emerge from the admin -
istration of test articles and help determine if these can be monitored, managed, or mitigated.
The use of in vitro models to identify potential safety concerns prior to conducting the GLP
study are encouraged but may not be possible.
Justification of dose
A range of doses together with appropriate vehicle control(s) are required in the design of
the pivotal toxicology study to correlate BD and target exposure with safety endpoints and to
establish a no observed adverse effect level (NOAEL) for clinical translation. Ideally, a range
of twoethree doses adequately separated and including an effective dose (ED) as determined
in the pharmacological studies, and multiple(s) above this are selected. The top dose may be
either an MFD or at the limit of manufacturing (e.g., maximal possible titer) depending on the
intended ROA and manufacturing characteristics. If dosed systemically, doses are typically
scaled by body weight and may be limited by total acceptable volume and infusion rate,
whereas in more confined anatomic regions such as the eye or brain, doses may be scaled
by total dose per unit volume, unit areas of tissue or per animal. Of note, while dosing is typi-
cally based on effective particle numbers e.g., titer, the total particle load should be cons id-
ered, as this may significantly contribute to the emergence of toxicities (Kishimoto and
Samulski, 2022).
Justification of delivery method
The GLP toxicology study should include a clear justification for the delivery method
and ROA that sufficiently replicates the in tended design for clinical use. For GTs in partic-
ular, careful attention needs to be paid to whether the administered product adheres or is
absorbed by the devices used to administer the test article. Stainless steel, g lass, and plas-
tics are known to adsorb viral particles to varying degrees. There are approaches to over-
come this issue e e.g., either preflushing needles with the formulation buffer to coat
surfaces or having the viral preparation suspended in an appropriate poloxamer such
as P-188 or use of dedicated precoated devices (Ketchum, 2006; Ramy et al., 2022). A sim-
ple benchtop experiment should be performed to evaluate the titer of the product before
and after it is delivered through the chosen devices at the same location and infusion rate
as intended for the pivotal study e.g., needle, catheter, etc. Data from these studies should
be included in the toxicology study as an appendix to provide confidence in the dose
administration.
Justification of the te st system
Unlike new chemical entities and other biologics, GTs do not require safety testing in
two species e.g., small and large laboratory animals, to determine the most sensitive toxi-
cologic species. Species selection for the safety assessment of GT products should be scien-
tifically justified based upon its ability to be transduced by the vector, predict the FIH
dose(s) and safety profile. It is important to select a species in which the vector BD or
drug exposure at the target dose adequately represent the exposure desired in the patient
population.
Nonclinical development 279
III. Specialty biologics and indications
Sensitivity to reducing and refining animal experimentation supports the use of a single
species so that investigators might consider hybrid studies with pharmacology and toxi-
cology endpoints in the animal disease model. While the use of large laboratory animals
such as nonhuman primates (NHPs) for safety testing helps in translating the dose used in
animals for human testing and may offer predictive value for human safety, it is not manda-
tory (Baldrick et al., 2023). There is precedent for successful regulatory submissions of
nonclinical packages with a single species, such as a rodent. The key is to ensure that if a sin-
gle species is used, there is clear justi fication that it supports an adequate characterization and
understanding of the pharmacology and BD, as well as toxicology, and benefit/risk for entry
into patients.
Additional considerations for choosing the most appropriate species can include phar-
macological responsiveness, immune tolerance toward the transgene product, and ROA
mimicking the clinical procedure. When an anti-transgene immune response is anticipated
in the chosen species, the use of species-specific surrogates may be warranted. If the selected
speciesisanaturalhostofthevirusfromwhichtheviralvectorisderived(e.g.,AAVfrom
NHPs), preexisting immunogenicity may significantly impact the BD and the safety profile
of the GT. Screening the animals for the presence of total or neutralizing antibodies against
the viral vector is then recommended before assigning the animals to a study (Sprangers
et al., 2003; Sumida et al., 2005; Gorovits et al., 2020; Baatartsogt et al., 2021; Kasprzyk
et al., 2022; Schulz et al., 2023). In some instances, with neurological or ocular ROA,
screening the animals may not always be warranted as nonclinical and clinical data suggest
that pr eexisting immunity may not significantly impact the vector’s safety and efficacy
(Bennettetal.,2012; Gray et al., 2013). If the chosen toxicology species differs from the spe-
cies used to perform the pharmacologic studies, preliminary work may be needed to ensure
that the BD of the vector and transgene expression in key on- and off-target tissues are
comparable.
Considerations for study designs, safety endpoints and safety pharmacology
In the design of toxicology studies, durationisanimportantparametertoconsider
when evaluating the safety profile of GT products, to ensure that three key phases are
covered: (1) acute responses related to vector administration, (2) onset of gene expression,
and (3) a recovery timepoint to capture toxicities related to cumulative exposure of the
transgene product itself. In specific cases, evaluating the reversibility, resolution, or
absence of progression of adverse events maybenecessary,eventhoughthisimplies
extending the duration of a study. Deciding upon these timelines p rimarily relies on
fundamental knowledge about the vector being used and existing vector BD data, trans-
gene expression, and viral shedding. Initial safety assessments incorporated into short-
term pilot studies may inform the overall safety profile of the vector, and suitable duration
of the pivotal GLP toxicology study (see Pharmacokinetics e Biodistribution, shedding, and
persistence section above).
Toxicity assessments should include in-life monitoring (clinical observations, body weight,
body temperature, food consumption, etc.), in-life clinical pathology (serum chemistries,
urine analyses, hematology and coagulation), other in-life evaluations such as safety pharma-
cology or specific study endpoints tailored to the GT program (e.g., immunogenicity), as well
9. Preclinical development of viral vector gene therapies280
III. Specialty biologics and indications
as terminal assessments such as BD in recommended tissues to confirm drug exposure at the
target (both genomic and transgene expression), and comprehensive histopathology.
In general, standalone safety pharmacology studies are not conducted for GT products un-
less there is a specific safety issue. In most cases, safety pharmacology endpoints are inte-
grated into the GLP toxicology study and may include electrocardiography, ophthalmic
examination, respiratory function, renal function inclusive of urinalysis, or behavioral or
neurological assessments.
Considerations for immunogenicity in toxicology studies
The administration of viral-based GT products can trigger an immune response, which
may imp act BD and transgene product expression, thereby decreasing exposure, and invalid-
ating safety outcomes (Ahi et al., 2011; Mingozzi and High, 2013; Shirley et al., 2020; Ertl,
2022; Yang et al., 2022). An initial immunogenicity risk assessment is generally recommended
before initiating the GLP toxicology study, summarizing current knowledge about the vector
(platform immunogenicity risk), dose, ROA, transgene product (expected tolerance in the
chosen toxicology species) and target patient population (evaluation of the seroprevalence
in the intended patient population). In most cases, humoral and cellular immune responses
against the viral vector are expected after systemic administration and will generally occur
within days or weeks after dosing, irrespective of ROA. Anti-capsid responses are generally
not considered to represent safety signals but may impact the total number of efficacious par-
ticles that reach the target cells. Depending upon the similarity between the human transgene
product and its homolog in the chosen toxicology species, or the subcellular localization of
the transgene (e.g., secreted vs. intracellular), an anti-transgene immune response can arise
and compromise the efficacy (transduction efficacy, duration of expression) and safety
evaluation.
Depending upon the viral vector and chosen genetic payload, early innate immune re-
sponses such as the activation of complement pathways or responses stimulated by the pres-
ence of viral RNA or DNA in transduced cells may arise (Shirley et al., 2020). In most
instances regulators ask for characterization of the cellular (T-cell activation) and humoral (to-
tal or neutralizing antibodies) immune responses to understand exposure of the GT and how
this may impact safety interpretations. For example, rapid clearance of the vector due to the
presence of a strong antibody responses may explain in part absence of active transgene at the
target and lack of any safety findings e thereby rendering the GLP to xicology study inade-
quate to properly character ize safety. A thoughtful risk assessment before any animal is
dosed can help determine the extent to which immunologic responses should be monit ored
and measured. A contemporary discussion of the immunogenicity findings in nonclinical and
clinical studies is provided in the section titled, Lessons learned from clinical trials to guide future
development below.
Developmental and reproductive toxicity (DART)
To date, developmental and reproductive toxicology studies have not been mandated in
support of GT products. However, guidance language acknowledges that the need for these
types of studies is dependent on the product type, target patient population, ROA, and vector
BD profile. If warranted, these studies tend to be conducted later in development, prior to
commercialization. If DART testing is not performed, a clear scientific justification needs to
Nonclinical development 281
III. Specialty biologics and indications
be provided to explain why testing is not informative for patient safety. No official guidance
on the strategy is currently available for DART studies for GTs, and each spons or is encum-
bered with engaging with the regul atory authorities to agree upon the best approach.
What we do know to date is that AAV serotypes 2, 5, 8 and 9 delivered either systemically
or into the gonadal tissues themselves, do not appear to transduce germ cells, but instead
preferentially transduce supporting cells (Jakob et al., 2005; Watanabe et al., 2018 ; Zhao
et al., 2020; Fonck et al., 2023). In male mice and rabbits, transduction appears to occur in Ley-
dig and Sertoli cells, whereas in female mice AAV transduces lutein and thecal cells (Rajase-
karan et al., 2018; Zhao et al., 2020; Kanatsu-Shinohara et al., 2022). While in general, these
data suggest AAV carries a low risk for developmental and reproductive toxicities in of itself,
the safety justification must also take into consideration the transgene and its relative risk.
Sponsors advancing their programs toward commercial approval should consider the
DART safety package that balances the intended patient population, transgene being
expressed, and the long-term effects. Early engagement with regulatory authorities can
help to avoid costly delays.
Genotoxicity: Insertional mutagenesis, carcinogenicity, and germline transmission
The risk of integration of the viral genetic payload into the host genome not only pertains
to integrating vectors such as retroviruses but has also recently emerged as a concern for
‘nonintegrating viral vectors’ such as AAVs (as discussed in the section above, Adeno-
associated vectors (AAV)). Until the emergence of hepatocellular carcinoma in mice following
systemic administration of AAV gene in neonates (Donsante et al., 2001, 2007), AAV was
considered nonintegrating. This is because recombinant AAVs typically exist as double
stranded concatemers, forming intranuclear episomes (Russell, 2007). Recent publications
have demonstrated that the disease context may greatly impact this risk in adult mice,
with the induction of liver injury (nonalcoholic fatty liver disease) promoting the occurrence
of hepatocellular carcinoma in the species (Dalwadi et al., 2021). Long-term studies in both
preclinical species as well as in patient biopsies, have reported that a small proportion of
AAV viral genomes (often fragmented) end up integrating in the host genome (Nowrouzi
et al., 2012; Kaeppel et al., 2013; Gil-Farina et al., 2016; Nguyen et al., 2021; Sabatino et al.,
2022; Martins et al., 2023; Greig et al., 2023; Batty et al., 2024) (see section below Insertional
Mutagenesis). To date, in the considerable number of patients that have been treated with
GTs, no causal association has been demonstrated between such events and the emergence
of malignancies.
In most instances, the insertion of the viral genome is not directed toward a specific DNA
site of the host, with each specific type of viral vector preferentially inserting into character-
istic regions e.g., within transcriptionally active regions for LV or transcriptional start sites for
gamma retroviruses (Milone and O’Doherty, 2018). If viral vectors are used to deliver gene
editing reagents such as nucleases, then additional assessments are required to ascertain if
the GT results in insertions (sometimes of the viral vector itself), deletions, and rearrange-
ments in the desired target tissues but also in off target tissues (Hanlon et al., 2019).
Profiling integration sites when using an integrating therapeutic viral vector is a regulatory
requirement, together with clear expectations of long-term 15-year follow-up in patients. If
sponsors are using an integrating vector, the safety package should include a clear strategy
to assess genotoxicity, including assays to profile viral genome insertion sites, potential
9. Preclinical development of viral vector gene therapies282
III. Specialty biologics and indications
translocations, genomic rearrangements, and chromosomal stability. These assays can be sup-
ported by the comprehensive histopathological assessment that will investigate the presence
of carcinogenic features in both target and nontarget tissues. For these programs, it is recom-
mended to engage early with regulatory authorities to ascertain if the proposed insertion site
risk assessment is acceptable and adequately supports patient safety. With the advancement
of novel sequencing technologies, the understanding of the field is increasing and will
certainly shape the regulatory environment. While this has not been a requirement for non-
integrating vectors, the possibility of vector integration and insertional mutagenesis should
be considered based on available nonclinical and clinical data for each specific product.
Translating nonclinical data to regulatory success
An ever-evolving regulatory landscape
Regulation of GTs continues to rapidly evolve with the scienti fic advances feeding the
development of the novel therapies in this space. The sheer number of products in the devel-
opment pipeline have put inordinate pressure on regulatory oversight in global geographies
and the innovative, unique scientific approaches in the design, manufacturing and testing of
these products have highlighted gaps in regulation that have the potential to impact patient
access to these life-chan ging products. Most countries do not have specific regulations for GT
products (ARM 2022 report (ARM, 2022)), but at least one ICH document, e.g., S12, has been
developed. GT specific guidance and “Points to Consider” documents published to date are
shown in Table 9.2.
To support the evaluation and regulation of GT products, countries have expanded their
existing medicinal product regulations and created subsets within existing legislation. The
adequacy of this approach will be tested in the coming years as a harmonized regulatory
framework that is robust but not unduly burdensome, given GT product complexity, is
needed. Notably, in January 2024, FDA took the first steps toward international regulation
of GT to treat rare diseases with the launch of a pilot program, “Collaboration on Gene Ther-
apies Global Pilot (CoGenT Global)” to encourage “regulatory convergence” across countries,
decrease costs and review times, and increase commercial viability of cell and gene therapies
to treat rare diseases (FDA, 2024b).
Regulations have typically lagged GT product development, as the inno vative science and
complex manufacturing processes created a need for different regulatory approaches than
what currently exists for biologic products. Early GT developers had no regulatory prece-
dents from approved products and few published guidance documents to aid and assist in
development decisions. Further, inconsistencies across published regulatory guidance docu-
ments and advice provided for the same product by regulators in differing geographies were
common. In addition, the exponential growth in the number of GT clinical trial applications
and the increased demand from developers for regul atory input and oversight has produced
a shortage of experienced regulators to provi de pragmatic guidance on these products. The
2020e23 COVID-19 pandemic also played a disruptive role in GT development activities
as global scientific and development efforts shifted regulator attention to products for
COVID-19 detection, prevention, and treatment.
Translating nonclinical data to regulatory success 283
III. Specialty biologics and indications
Even in situations where the regulatory pathways seem confusing or there are contradic-
tory regulatory development pathways, GT marketing approvals are ever-increasing in the
US and EU. The European Commission (EC) approved Upstaza and Roctavian in 2022 to
treat aromatic
L-amino acid decarboxylase (AADC) deficiency and Hemophilia A, respec-
tively. FDA approved Hemegenix for Hemophilia B in late 2022 with the EC following suit
early in 2023. Skysona for the treatment of early a ctive cerebral adrenoleukodystrophy
(CALD) was approved by FDA in September of 2022. In 2023, FDA has also approved Roc-
tavian for Hemophilia A, and Elevidys for Duchenne muscular dystrophy. This is a record
number of approvals as up until 2024, there had never been more than 1 GT approved in
a single year (see Table 9.1)(ARM, 2022; ASGCT, 2024).
Regulatory bodies from all countries recognize the life-changing potential of GTs and have
committed resources to expand and accelerate regulatory activities in support of GT develop-
ment. One exa mple is the recent decision by FDA’s Center for Biologics Evaluation and
Research (CBER), the regulatory body governing GT products to elevate the Office of Tissues
TABLE 9.2 Gene therapy clinical development regulatory guidance documents (FDA and EMA).
Title of guidance document
(CART and genome editing not included) Issue date Authority
Studying multiple versions of a cellular or gene therapy product in an early-phase clinical trial;
guidance for industry (FDA, 2022k)
2022 FDA
Master protocols: efficient clinical trial design strategies to expedite development of oncology
drugs and biologics guidance for industry (FDA, 2022i)
2022 FDA
Human gene therapy for neurodegenerative diseases; guidance for industry (FDA, 2022h) 2022 FDA
Human gene therapy for hemophilia; guidance for industry (FDA, 2020b) 2020 FDA
Human gene therapy for rare diseases; guidance for industry (FDA, 2020c) 2020 FDA
Human gene therapy for retinal disorders; guidance for industry (FDA, 2020d) 2020 FDA
Expedited programs for regenerative medicine therapies for serious conditions (FDA, 2019b) 2019 FDA
Considerations for the design of early-phase clinical trials of cellular and gene therapy
products; guidance for industry (FDA, 2015a)
2015 FDA
Guideline on the quality, nonclinical and clinical aspect s of gene therapy medicinal products
(EMA/CAT/80183/2014) (EMA, 2014)
2014 EMA
Reflection paper on management of clinical risks deriving from insertional mutagenesis (CAT/
60436/2007) (EMA, 2013)
2013 EMA
Reflection paper on quality, nonclinical and clinical issues relating specifically to recombinant
adeno-associated viral vectors (CHMP/GTWP/587488/07) (EMA, 2010)
2010 EMA
Guideline on the safety and efficacy follow up and risk management of advanced therapy
medicinal products (EMEA/149995/2008) (EMA, 2008a)
2008 EMA
Guideline on follow-up of patients administered with gene therapy medicinal products
(EMEA/CHMP/GTWP/60436/2007 (EMA, 2007)
2007 EMA
Guidance for industry gene therapy clinical trials e observing subjects for delayed adverse
events (FDA, 2006)
2006 FDA
9. Preclinical development of viral vector gene therapies284
III. Specialty biologics and indications
and Advanced Therapies (OTAT) to a new “super” office within CBER to address the
growing resource demand and workload (FDA, 2022j). OTAT has been renamed the Office
of Therapeutic Products (OTP) and is part of FDA’s commitments under the Prescription
Drug User Fee Act (PDUFA) VII agreement for fiscal years 2023e27. The proposed changes
leading to the creation of OTP are intended to improve functional alignment, increase review
capabilities, and enhance expertise on these new therapies. More comprehensive regulation
within the GT space and more staff to develop, implement and apply review policies and
guidance are likely to correspond with increased clinical trial initiations with the pros pect
of more approvals of GT for marketing. In addition, the US, EU and Japan implemented expe-
dited pathways for GTs in development to treat patients with high unmet medical need. Spe-
cifically, the FDA’s Regenerative Medicine Advanced Therapy (RMAT; established in 2017)
for cell and GT products and Breakthrough Therapy (BT; established in 2012) designations
are in place in the US, while the EU and Japan have established the Priority Medicines scheme
(PRIME; established in 2016) and SAKIGAKE (established in 2014) designations, respectively.
While the levels of evidence needed to qualify for these designations is relatively high, they
provide means to ensure a solid path for develop ers in working with regulators to accelerate
the development of these life-changing products for patients with high unmet medi cal needs
throughout a GT product’s life cycle.
As the majority of GT products in development target rare diseases with small patient
populations, most rare diseases are not selected for GT development because the financial op-
portunity is often not viable for sustaining commercial entities (Hughes et al., 2005; Smith
et al., 2022). In 2017, the FDA, National Institutes of Health (NIH) and multiple public and
private organizations launched the Accelerating Medicines Partnership (AMP) in an effort
to streamline the development process for rare disease GTs. The Bespoke Gen e Therapy Con-
sortium (BGTC) aims to collect and provide information on basic and clinical research,
manufacturing, production, and regulatory requirements for GTs intended to treat ultra-
rare disease populations (<50e60 patients worldwide) to provide a blueprint for develop-
ment of treatments for diseases where the patient populations for product developmen t
are not financially viable (Brooks et al., 2024; FNIH, 2024). The bulk of the consortium’s
work is to develop repeatable, optimized processes that will allow patients access to a FIH
GT clinical trial. To that end, manufacturing and nonclinical experts are working to establish
a consensus for GT product development requirements in those disciplines. The FDA is work-
ing with the BGTC to create a publicly available, standard regulatory submission dossier
populated with FDA-vetted relevant preclinical and GT manufacturing information so that
interested groups, particularly patient groups, can refer to the completed, publicly available
regulatory submission rather than redo the work on their own. One year into the initiative,
the partnership has expan ded to include the American Society of Gene and Cell Therapy
(ASGCT), and selection of eight diseases for clinical trials is moving forward (FNIH, 2023).
Early manufacturing and nonclinical testing are set to begin in year two. With an increasing
demand for standardization to allow regulators to make meaningful comparisons of informa-
tion from multiple similarly designed products, the BGTC deliverable has the potential to
revolutionize the way information of many GT products are reviewed.
The pressure on regulatory bodies to harmonize and implement solutions to address issues
such as varying review timelines, documentation requirements, study requirements, and reg-
ulatory pathways persists worldwide. Creative and flexible regulatory approaches that
Translating nonclinical data to regulatory success 285
III. Specialty biologics and indications
Соседние файлы в папке Библиотека им академика М.И. Перельмана