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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5394_Библиотеки_им_академика_М_И_Перельмана
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19 Regulatory Considerations in Product Development for Back of the Eye
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these trials as needed. After the successful completion of Phase II clinical trials, a
thorough evaluation of all the available data should be done to obtain crucial understanding of the drug’s formulation feasibility and characteristics, safety profile and
safety margins, dose–response relationships, and pharmacokinetics and metabolism. This evaluation also helps in choosing the correct doses that have the highest
probability of success for potential future Phase III clinical trials. The decision to
proceed with Phase III clinical trials that are generally long, expensive and involve
a significantly higher number of patients should be made following this evaluation.
The FDA requires at least two successful Phase III studies powered adequately to
demonstrate statistically significant proof of the claimed therapeutic efficacy.
Additional data from reproductive and developmental toxicity studies are needed
before initiating Phase III clinical trials. Once Phase III clinical trials are complete
and the sponsor has enough confidence in the statistical significance of the results,
a NDA can be filed with the FDA for marketing authorization of the drug.
During the course of this regulatory process to obtain product approval, the FDA
offers several mechanisms for the sponsor to consult with the agency before proceeding with the clinical trials. These come in the form of Type A, Type B, or Type
C meetings between the sponsor and the FDA. These meetings can be officially
requested by the sponsor and are granted by the FDA based on urgency of the matter
and resources available to the agency. A comprehensive description of the types of
meetings, procedures for requesting these meetings, content and timing of submission of information packages, and the procedures for the conduct of these meetings
are detailed in the Guidance document prepared by the Review Management
Working Group comprising individuals in the Centers for Drug Evaluation and
Research (CDER) and Biologics Evaluation and Research (CBER) at the FDA in
February 2000.
19.3 Considerations for Back of the Eye Treatments
None of the health agencies around the world have established a specific set of
guidelines to assist in development of drug products for treatment of diseases of the
back of the eye. However, assessing the quality of formulation development (chemistry, manufacturing, and control – CMC), ensuring the safety and efficacy of the
drug product via nonclinical testing, and obtaining clinical evidence of the safety
and efficacy using a rigorous clinical development program are the cornerstones of
any drug development program and apply to the development of drug products for
treatment of back of the eye diseases as well. The overall drug product approval
process is similar to that mentioned in the previous section. The CMC section is
geared towards assuring the quality of the drug substance and the drug product and
comprises, at a minimum, documents supporting the following:
1. Description of the synthetic process for manufacturing the drug substance.
2. Physicochemical properties of the drug substance.
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3. Development and validation of analytical methods for the drug and potential
impurities.
4. Details on the composition and characterization of the formulation (composition,
sterility testing, endotoxin testing, pH, etc.).
5. Proof of stability of the drug substance and the drug product.
6. In vitro release rates from the formulation.
All drug products designed for intraocular injection should be completely sterile
and free of endotoxin to prevent any potential complications due to infections and/
or endophthalmitis. It is the responsibility of the sponsor to demonstrate that the
sterilization procedures do not change the nature and composition of the drug product. The best way to avoid any complications from this is to treat the drug product
used in nonclinical studies in the same way as the potential commercial product.
This accounts for any chemical changes or residual by-products of sterilization and
evaluates the corresponding safety risk in nonclinical species before progressing
into clinical trials. Furthermore, since longer duration of action is preferred for
drugs delivered to the posterior segment of the eye (to reduce the frequency of
intraocular injection), most of the drug delivery systems need to demonstrate consistent release rates to ensure steady delivery of the drug to the target tissue over the
intended duration. The FDA has stated that the release rates should be within
± 10%
of nominal. If the release rates fall out of specification at a later stage in the development program, the initial preclinical and clinical study data could be rendered
invalid (Gryziewicz and Whitcup 2005). The use of Good Manufacturing Practices
(GMP) is critical during this phase.
The IND-enabling nonclinical studies are part of a standardized pharmacology,
pharmacokinetics, and toxicology package required by the FDA (as well as other
health agencies around the world). The aim of these studies is to demonstrate the
safety and efficacy characteristics of the drug product in acceptable in vitro and
in vivo models. The scope and nature of the studies should be based on sound scientific principles and astute scientific judgments based on all the available data.
The standard pharmacology, pharmacokinetics, and toxicology package required
for any drug typically includes but is not limited to the following:
1. Pharmacology
(a) Primary pharmacodynamics
(b) Secondary pharmacodynamics
(c) Safety pharmacology
(d) Pharmacodynamic drug interactions
2. PKDM
(a) Analytical methods and validation
(b) Absorption (via the intended route of administration)
(c) Distribution
(d) Metabolism
(e) Excretion
(f) Pharmacokinetic Drug Interactions
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3. Toxicology
(a) Local tolerance
(b) Single dose toxicity
(c) Repeat dose toxicity
(d) Genotoxicity
(e) Carcinogenicity
(f) Reproductive and developmental toxicity
In addition to the nonclinical toxicology studies, the nonclinical pharmacokinetic
studies are crucial during the development of drug products for back of the eye
diseases since it is very difficult to obtain clinical ocular samples. Therefore a good
understanding of the target tissue(s) and development of a good pharmacokinetic–
pharmacodynamic (PKPD) model based on drug concentration in the target tissue(s)
goes a long way in scaling up the findings from nonclinical species (most likely
rabbit, dog, or monkey) to humans. For retinal diseases like macular degeneration,
the drug concentration at the retinal pigment epithelium, or choroid is important
while for retinal diseases like proliferative vitreoretinopathy, vitreous levels may be
the target (Gryziewicz.
2005).
A detailed description of these nonclinical studies is provided in Section C
(Preclinical Development) of this book and most of these studies are conducted
under the auspices of Good Laboratory Practices (GLP). Depending on the nature
and marketing status of the drug, a formal request to waive some of these studies
can be made by the sponsor to the agency based on scientific justification. For
example, if the drug has been previously marketed for nonocular indications (systemic use), a fair amount of systemic pharmacokinetics, metabolism, and toxicity
data can possibly be obtained from the literature, providing the option of utilizing
the 505(b)(2) approval route (FDA Draft Guidance). This data combined with the
potential lack of significant systemic exposure following intraocular administration
(high safety margins) could be used to justify a waiver for some of the nonclinical
studies such as systemic distribution and metabolism studies, chronic systemic toxicity studies, reproductive and developmental toxicity studies, and carcinogenicity
studies. However, if the drug is a new chemical entity (NCE) with unknown safety
characteristics, the full complement of studies may be needed for registration filing.
These concerns can be discussed at Pre-IND or end of Phase II (EOP2) meetings
between the sponsor and the agency. The approval of such requests is completely at
the discretion of the agency. During the meeting, the sponsor may request a waiver
of some studies. If granted, these waivers can save the sponsor a significant amount
of time, money, and resources during the drug development process without jeopardizing the integrity of the overall submission package.
The clinical development of drug products is carried out in accordance with
Good Clinical Practice (GCP) that set the standard for ethical and scientific quality
for all aspects of clinical trial conduct and reporting. Typically, the sponsor progresses through Phase I, Phase II, and then Phase III clinical trials in a logical
sequential manner with the data from each trial guiding the design of the next larger
and more definitive trial. But with increasing cost and time of clinical trials, some
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STAGE 1: Open Label Staggering Dose Escalation
Cohort 1
Microdose or
Sham
Cohort 2
Low dose
*Dose escalation may be stopped following review of the safety data from each cohort
Cohort 3
Mid dose
Primary
Endpoint
Stage 2
Sham
Optimized low dose
Optimized
Dose Levels
Based on
Stage 1
Results
Optimized high dose
Optimized mid dose
Cohort 4
High dose
STOP
ESCALATION*
STOP
ESCALATION*
STOP
ESCALATION*
STAGE 2: Masked Randomized Dose-Response
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Fig. 19.1 Example of a two-stage Phase I/II clinical trial design
sponsors prefer conducting Phase I/II trials in a multistage fashion. One example of
such multistage trial is shown in Fig. 19.1. In addition, the initial multistage clinical
trials can be designed as proof-of-concept trials to exhibit efficacy over a shorter
period of time even though the ultimate goal is for a longer duration (ideally ³ 6
months to 1 year). If these shorter trials demonstrate the activity of the drug when
administered via its intended route of administration, it provides the sponsor with
confidence to proceed with larger, expensive, and longer trials (Phase III) aimed at
demonstrating the efficacy for a longer duration.
Phase III clinical trials are designed to demonstrate one of the following
outcomes:
1. The drug product is superior to a placebo.
2. The drug product is equivalent or noninferior to an approved marketed product
for similar indication.
3. The drug product has superior efficacy and/or safety compared to an approved
marketed product for similar indication.
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19.4 Adaptive Trial Design
The Office of Biostatistics and the Office of New Drugs in CDER in conjunction
with CBER released a Draft Guidance document on “Adaptive Design Clinical
Trials for Drugs and Biologics” in February 2010 that clearly underscores the grow-
ing interest and push towards adaptive design clinical trials to make the studies
more efficient and more informative. The Draft Guidance defines an adaptive design
clinical study as a study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based
on the analysis of data (usually interim data) from subjects in the study. Analyses of
the accumulating data are performed at prospectively planned timepoints within the
study, can be performed in a fully blinded manner or unblinded manner, and can
occur with or without formal statistical hypotheses testing. In other words, adaptive
clinical trials will empower the sponsors and investigators to change the design or
analyses of clinical trials based on insights obtained by examination of the accumulated data at an interim point in the trial. Since this is a relatively new concept, the
greatest interest in this approach has been in the adequate and well-controlled studies intended to support marketing a drug. It is always in the best interest of the sponsor to plan the adaptation in advance (being prospective) and discuss the details of
this adaptation with the FDA in order to avoid any potential complications that may
affect the validity of the interim analysis, the changes implemented the following
interim analysis or the integrity of the entire clinical study itself. It would be devastating if the entire study is deemed invalid due to issues such as introduction of bias
based on an unplanned action by the sponsor.
Adaptive Design clinical trials offer some key advantages over the conventional
design clinical trials. Planning a well-designed study to support market registration
of a drug requires adequate knowledge on a variety of parameters such as event
rates, variance, discontinuation rates, etc., and these are generally incorporated in a
conventional design clinical trial as assumptions or “best estimates.” If these
assumptions are incorrect, the study may fail to achieve its goal. Therefore to
increase the likelihood of success, the study may be designed with higher number of
patients or duration resulting in increased cost and time. Additionally, it may also
lead to instances where the patients in the suboptimal dose group continue to get
dosed for the entire duration of the study providing no meaningful data and therefore increasing the cost of the study and reducing the overall efficiency. An adaptive
design clinical trial takes this into account and eliminates some of these issues by
including an interim analysis at predetermined timepoints. Following interim analysis of the dose response or other parameters, a decision can be made on whether
the suboptimal dose group should continue to be dosed or discontinued (will dosing
this group provide any additional value). Discontinuation may lead to a decrease in
cost and time of the study without reducing the informativeness. This can lead to
efficient allocation of resources and potentially the collection of more data on more
parameters than would be possible with the conventional design.
Even though interactions by the sponsor with the FDA are commonplace during
the course of a drug development program, these become even more crucial when
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the sponsor decides to use an adaptive design for conducting a clinical trial. Due to
the increased complexity of the adaptive design, it is important that the sponsor has
earlier and more extensive interactions with the FDA. If the study is an exploratory
study, the FDA will focus upon the safety of the study participants and will consider
the relevance of the parameters being examined (dose response, endpoints, biomarkers, etc.) to guide the design of later studies. The efficacy measurements are
outside the realm of this review and will be focused on during the late stages of drug
development. The assessment of the adaptive design features by the FDA gets more
extensive during the late stages of drug development. This review still focuses on the
safety of study participants and now includes evaluation of the assessment of safety
and efficacy to ensure that the study data will be of sufficient quality and quantity to
inform a regulatory decision. It is important to note that the FDA will generally not
be involved in examining the interim data used for the adaptive decision making and
will not provide comments on the adaptive decision while the study is ongoing. In
addition, the acceptance of adaptive design at the protocol design stage does not
imply its advance concurrence that the adaptively selected choices will be optimal
choices. An overview of the regulatory mechanisms for obtaining formal approval,
substantive, feedback from FDA on design of the later stage trials and their place in
drug development program are described in the Sect.
19.3 of this chapter.
19.5 Drug-Device Combinations
Since local delivery of the drug to the posterior segment of the eye typically requires
intraocular injections, devices such as needles and syringes play a prominent role in
facilitating such delivery. As a result, the new therapeutic products may not be classified exclusively as a drug or device but rather a “combination” product.
OZURDEX™, a dexamethasone biodegradable Intravitreal implant marketed by
Allergan Inc, is one such example of a combination product. The drug product is a
rod-shaped intravitreal implant that comes preloaded into a standard 22-G thin wall
hypodermic needle of a single-use applicator that delivers the implant directly to the
posterior segment of the eye. CDER, CBER, and the Center for Devices and
Radiological Health (CDRH) have entered into agreements clarifying the product
jurisdictional issues per Part 3 of Title 21 of the Code of Federal Regulations
(Product Jurisdiction). The sponsor of the drug application (IND, NDA, or any other
premarket or investigational application) needs to contact the appropriate center in
the agency to confirm coverage and discuss the application process. Even though
the application is made to a single center in the agency, it does not preclude the
center from requesting assistance from the other centers to evaluate the appropriate
parts of the application, as needed.
According to 21 CFR Part 3, the primary mode of action of the product needs to
be clarified in order to determine which center will take the lead role in reviewing
the premarket application. Here are some examples:
1. If the primary mode of action of the product is that of a drug (other than biologi-
cal products), then CDER will have primary jurisdiction for the application
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review. A prefilled delivery system (e.g., OZURDEX™) is a good example of
this combination product where the implant is preloaded into a single-use delivery
applicator but the main purpose of this system is to deliver the implant into the
posterior segment of the eye.
2. If the primary mode of action of the product is that of a drug and the drug sub-
stance is a biological product, then CDER will have primary jurisdiction for the
application review. An example would be a solution of any biological product
(such as LUCENTIS™) provided with an unfilled syringe and needle, with the
intention of using the unfilled syringe and needle (device) for delivering the drug
(in this case LUCENTIS™). If the device has not been previously approved by
CDRH, then the jurisdiction will be divided between the two centers; CDRH for
the device and CDER for the drug.
3. If the product includes a drug–device combination that is intended primarily to
perform as a device, then CDRH will have primary jurisdiction for the applica-
tion review. A good example of this is a surgical draper coated with an antimicro-
bial agent, or bone cement containing an antimicrobial agent.
4. If the product includes a drug–device combination that is intended primarily to
perform as a drug, then CDER/CBER will have primary jurisdiction for the
application review based on whether the drug is a small molecule entity or a
biologic. For example, skin prep pads with antimicrobial agent.
19.6 Product Summary Basis of Approval Reviews
A better understanding of the regulatory programs for back of the eye treatments can be
obtained by reviewing the summary basis of approvals (SBAs) for products that have
been evaluated and approved by the FDA and/or other health agencies around the world.
A review of these SBAs will help the reader understand the nature of CMC, nonclinical
and clinical studies that form the template for a global development plan for the investigational new drug; and even though every drug is unique and may need some tweaking
of plan (some additional studies may need to be conducted), the overall template will
remain relatively similar. The SBA for MACUGEN™ (Pegaptanib sodium injection)
has been discussed by Gryziewicz (
(Dexamethasone biodegradable intravitreal implant – a small molecule corticosteroid)
and LUCENTIS™ (Ranibizumab injection – a humanized antibody). The reader is also
encouraged to review the SBAs of other products on the FDA website.
2005). Here we review the SBAs for OZURDEX™
19.6.1 OZURDEX™
OZURDEX™ is a dexamethasone containing intraocular drug delivery system
developed by Allergan Inc for treatment of macular edema following branch retinal
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vein occlusion (BRVO) or central retinal vein occlusion (CRVO). It is a biodegradable
implant containing 0.7 mg dexamethasone that is injected into the vitreous
humor using a specifically designed injector. On 10 January 2005, the agency
granted Allergan with a Fast Track Designation for the dexamethasone Intravitreal
implant stating that there were no approved drug products indicated for patients
with macular edema secondary to BRVO or CRVO at that time. The drug product is
a rod-shaped intravitreal implant loaded into a standard 22-G thin wall hypodermic
needle of a single-use applicator that delivers the implant directly to the posterior
segment of the eye. It contains the active drug in a biodegradable poly (d,l-lactideco-glycolide) (PLGA) matrix. Consistent in
vitro release rates were demonstrated
and these showed good correlation with the in vivo release rates in rabbits and monkeys. Additionally, the sterility and endotoxin limits were specified and accepted
by the agency.
Dexamethasone is a synthetic derivative of hydrocortisone that acts as a potent
anti-inflammatory agent and inhibits the expression of VEGF leading to an inhibition of VEGF-induced vascular leakage in a rabbit model of blood-retinal and
blood-aqueous barrier breakdown (Edelman et al., 2005). This was confirmed in a
10-week study evaluating the primary pharmacodynamics of the dexamethasone
intravitreal implant. A dose-dependent inhibition of VEGF-induced blood-retinalbarrier (BRB) breakdown was observed with 0.35 and 0.7 mg dexamethasone
implants with the higher dose producing a more pronounced inhibitory effect compared to lower dose.
In addition to the pharmacology studies, the submission included a condensed
nonclinical safety program (PKDM and toxicology studies) because dexamethasone had been marketed in the United States for decades and its systemic ADME
(absorption, distribution, metabolism, and excretion) and toxicology profile had
been well established. Five single dose ocular absorption and distribution studies
with the dexamethasone implant were conducted in rabbits and one single dose
study was conducted in monkeys. Dexamethasone concentrations were generally
lower in monkeys compared to rabbits and lasted for a longer period of time with
the implant releasing >90% dexamethasone by 3 months and containing detectable
levels in the vitreous humor up to 6 months. These concentrations were higher than
the EC50 values obtained from cell-based potency assays supporting the 6-month
clinical dosing interval. In vitro, dexamethasone did not bind to synthetic melanin
suggesting that it does not accumulate in pigmented ocular tissues following
repeated dosing. Tissue distribution studies using radiolabeled dexamethasone containing implants showed that the drug distribution in the posterior segment of the
eye was relatively higher than its distribution in the anterior segment of the eye following intravitreal injection. Dexamethasone also exhibited negligible metabolism
in an in
vitro study using human ocular tissues and in in vivo ocular metabolism
studies in rabbits and monkeys. Since the characteristics and metabolism of the
matrix PLGA polymers had been extensively studied during the past few decades
and these polymers had been approved by the FDA for human use, no additional
studies were conducted to characterize the metabolism of these polymers. Since the
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systemic use of dexamethasone had been reported for several decades, systemic
distribution, metabolism, and excretion studies were not conducted. In addition, the
plasma concentrations of dexamethasone following intravitreal administration were
minimal, alleviating any concerns of systemic side effects.
Ocular and systemic safety of the dexamethasone implant was evaluated in three
single dose toxicity studies in rabbits and in repeat dose toxicity studies each (two
injections, 3 months apart) in rabbits and monkeys. Even though some transient
and expected dexamethasone-related systemic adverse effects in rabbits were
observed, the repeat dose toxicity study in monkeys did not exhibit any significant
ocular or systemic toxicity at doses up to two 0.7
mg implants, 3 months apart. The
0.7 mg dose was substantially lower than the maximal doses in animal studies
reported without adverse ocular findings for single intravitreal injection (4.8 mg) or
for implanted sustained release dexamethasone devices (5.0 mg). Furthermore,
dexamethasone had been widely used in ophthalmology for many decades (Gordon
1959a, b). Since the plasma concentrations of dexamethasone following intravitreal
administration were minimal and the systemic use of dexamethasone had been well
documented, additional toxicity studies via the systemic route of administration,
genetic toxicology studies, reproductive toxicology studies, and carcinogenicity
studies were not conducted because the data were either not needed (due to adequate systemic safety margins following intravitreal injection) or was available in
the literature, resulting in significant savings of time, money, and resources.
Furthermore, since the use of PLGA polymers was well documented in humans
with no safety concerns, no toxicity studies were needed to prove the safety of the
PLGA matrix alone.
The clinical development program included Phase I emergency and compassionate use studies, Phases I and II dose ranging trials and two Phase III multicenter,
masked, randomized, sham-controlled, safety and efficacy studies in patients with
macular edema following BRVO or CRVO. The clinical data showed that 0.7 mg
implant had greater efficacy and longer duration of effect than the 0.35 mg implant
suggesting a dose response. The safety endpoints (mostly class effects related to
steroids) did not exhibit a dose response and the overall incidence of adverse events
was significantly higher when compared to sham, but was not statistically significant between the two dose groups. Overall there was substantial evidence of safety
and efficacy to file an NDA application with the FDA. Following the NDA application, OZURDEX™ was approved in June
2009.
In addition to these studies, the sponsor requested a Pediatric Waiver at one of
the two pre-NDA meetings based on the justification that pediatric studies with
dexamethasone implants are highly impractical due to the fact that macular edema
associated with BRVO or CRVO is mainly found in adults and the number of pediatric patients with this indication is very small. This request was granted by the
FDA. The sponsor also held additional meetings with the FDA that included a
pre-IND meeting, an EOP2 clinical trial meeting , clinical meetings and discussions
throughout the drug development program to obtain relevant guidance on the
nonclinical and clinical plans.
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19.6.2 LUCENTIS™
LUCENTIS™ (Ranibizumab) is a recombinant, humanized monoclonal IgG1 antibody antigen-binding fragment (Fab) designed to bind and inhibit all active forms
of human VEGF and indicated for neovascular (wet) ARMD. It is approximately 48
kilodaltons (kDa) and is produced by an Escherichia coli expression system. It is
administered as a 0.05-mL (0.5 mg) intravitreal injection of the sterile, colorless to
pale yellow solution once a month. In pharmacology studies, ranibizumab showed
high binding affinity to different isoforms of rhVEGF. This was confirmed in a
guinea-pig skin model where ranibizumab significantly inhibited VEGF-induced
vascular permeability in a dose-dependent manner.
Analytical methods including ELISA were developed to monitor the drug concentrations as well as antibodies against ranibizumab in various tissues and blood.
The nonclinical ADME studies included rabbit and monkey distribution studies
following intravitreal administration of the drug and a distribution study in rabbits
evaluating the pharmacokinetics of LUCENTIS™ following subconjunctival,
intracameral, and intravitreal administration. Ranibizumab was absorbed in most
of the ocular tissues (vitreous humor, retina, aqueous humor, ICB, corneal endothelium) and serum in both rabbits and monkeys with elimination half-life of 2–3
days. The serum concentration was minimal and the maximal separation between
the vitreous humor concentrations and serum concentrations was observed with
intravitreal administration compared to subconjunctival and intracameral administration suggesting that the intravitreal route is the better route of administration.
Ranibizumab elicited an antibody response in the vitreous humor and serum in
rabbits but not in monkeys. In an effort to extrapolate the results to humans, the
sponsor developed a pharmacokinetic model to predict the retina and serum exposure of ranibizumab under simulated dosing regimens after intravitreal and intravenous administration. The nonclinical toxicology package consisted of local
tolerance studies in rabbits and four repeat dose toxicology studies in monkeys
ranging in doses from 0.25 to 2.0
were conducted following a single intravitreal injection of the drug at 2.0 or 2.5 mg/
eye followed by a 7-day observation. Ocular inflammation was observed in these
animals. In the repeat dose toxicology studies in monkeys, dose-related inflammatory responses were observed in the anterior and posterior chambers at all doses,
possibly due to the lyophilized nature of the test article and suggesting that monkey
is the more sensitive model; however, these were transient and mostly reversible.
None of the animals exhibited any drug-induced systemic toxicity. The antibody
did not exhibit any cross reactivity to human tissues and was compatible at up to
20 mg/mL with human and monkey serum and plasma and human vitreal fluid.
Since the serum concentrations of the drug following intravitreal administration
were deemed negligible, genetic toxicity studies, carcinogenicity studies, and
reproductive and developmental toxicity studies were not conducted at the time of BLA
(Biological License Application) submission. Since the reproductive and developmental toxicity studies were not conducted, the review indicated that ranibizumab
mg/eye. The local tolerance studies in rabbits
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