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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5915_Библиотеки_им_академика_М_И_Перельмана
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Syringeability: Syringeability is an important factor to be considered for suspen-
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18.3.2.2 In Situ Forming Suspensions, Selection of Drug Form for
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Suspension, and Polymeric Microparticle Suspension
In situ forming suspensions and selection of drug form:
Polymeric microparticles: Microparticles prepared using biodegradable polyester
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18.3.2.3 Clinical Studies on Safety
18.4 Conclusions
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Acknowledgments This work was supported by the NIH grants R01EY018940 and
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References
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Chapter 19
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Regulatory Considerations in Product
Development for Back of the Eye
Ashutosh A. Kulkarni
Abstract This chapter strives to provide an understanding of the overall drug
product approval process and highlights the key points that a sponsor needs to focus
on in order to successfully develop and market a posterior ocular segment drug.
Furthermore, the chapter reviews the product summary basis of approvals for two
recently approved and marketed products namely Ozurdex™, a dexamethasone
containing intraocular drug delivery system for the treatment of macular edema
following branch or central retinal vein occlusion (BRVO or CRVO) and Lucentis™,
a recombinant, humanized monoclonal IgG1 antibody antigen-binding fragment
(Fab) indicated for neovascular (wet) age-related macular degeneration (ARMD).
The importance of scientific dialogue between the sponsor and the corresponding
health agency is emphasized and encouraged.
19.1 Introduction
An increasingly aging population around the world and specifically in the United
States has led to an increased occurrence of a variety of ocular diseases that
cause either ocular discomfort, debilitating visual impairment, or in some cases
complete blindness. Some of the most common diseases among these include
cataract, glaucoma, diabetic macular edema, and age-related macular degeneration (ARMD). The incidence and prevalence of these conditions have been
reviewed by Clark and Yorio (2003). The prevalence of blindness is expected to
significantly increase during the next decade (Ghodes et al. 2005). The pharmaceutical industry has taken note of this significant unmet need and is investing
A.A. Kulkarni (*)
Department of Pharmacokinetics and Drug Disposition, Allergan Inc, Irvine,
CA 92612, USA
e-mail: Kulkarni_Ashutosh@Allergan.com
U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye,
AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_19,
© American Association of Pharmaceutical Scientists, 2011
469
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heavily in the development of safe and effective drug candidates for treatment of
these diseases, including the treatment of posterior segment diseases. The drug
candidates include vascular endothelial growth factor (VEGF) inhibitors, receptor tyrosine kinase (RTK) inhibitors, corticosteroids, growth hormone inhibitors,
and others (e.g., integrin inhibitors, Sdf1/CXCR4 pathway inhibitors, nACh
receptor antagonists, and pigment epithelium-derived factor gene therapy)
(Marra et al. 2007).
In addition to developing safe and effective drug candidates, their delivery to
the target tissues is also of critical importance. Drugs can be delivered to the eye
following local or systemic administration. Local administration via the topical
ocular route results in very low bioavailability limiting this route to mainly treat
the diseases of the anterior chamber. This is mainly because the drug has to cross
penetration barriers, is subject to rapid clearance from the tear film and has to
travel against the intraocular fluid flow gradient (vitreous to aqueous) if administered topically. Scientists are still attempting to use this route but many attempts at
using this route for drug delivery to the back of the eye have failed. For the posterior segment diseases such as ARMD, systemic administration, intravitreal injection or periocular administration provide feasible alternatives. However, systemic
administration has its own set of challenges including the need to penetrate the
blood-retinal barrier (BRB), avoiding any efflux transporters present on the retinal
surface, and most importantly exposing the systemic circulation to high drug concentrations and the potential for systemic side effects. For this reason, systemic
administration is not a favored route for treating diseases of the back of the eye.
Intravitreal administration and periocular routes of administration are currently
the most preferred routes for delivering the drugs to the back of the eye. The different anatomical locations for administration of a variety of drug delivery systems for posterior segment diseases are reviewed by Lee and Robinson (2009).
Therefore, in addition to developing safe and effective drug candidates, it is important to devise innovative, minimally invasive techniques to deliver these drugs to
the back of the eye so that they can effectively reach the target tissues, such as the
retina, provide therapeutic concentrations at these target tissues and improve
patient compliance. These issues have been discussed in detail in the earlier chapters of this book.
To date, regulatory guidance specifically geared towards the development of posterior segment therapies has not been issued. In addition, differences exist among
the various health agencies worldwide and this need to be taken into account during
development since most drugs are developed with the intent of marketing them
worldwide, not just in the United States. Therefore it is very important to have a
global development plan in place before embarking on the long and expensive journey of conducting preclinical and clinical studies to support market registration.
The global development plan is an important document that provides a roadmap for
executing the various phases of drug development in a well coordinated, timely, and
effective manner. It is also critical that the pharmaceutical company (sponsor) work
closely with the regulatory agencies to assure that the development program will
meet the expectations and criterion set forth by the agencies.
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19 Regulatory Considerations in Product Development for Back of the Eye
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19.2 Drug Product Approval Process
Every drug must be approved by the country’s health authority before it can be
marketed in that country. In the United States, that health authority is the US Food
and Drug Administration (FDA). The commissioner of the FDA reports to the
Secretary of the Department of Health and Human Services. The FDA has publicized federal regulations based on the Federal Food Drug and Cosmetic Act that
was passed in 1938 and its amendments that provide the basic requirements for
obtaining approval of a New Drug Application (NDA). Chapter 1, Title 21 of the
Code of Federal Regulations (21 CFR) covers the US federal regulations that govern the testing, manufacture and sale of pharmaceutical agents, and medical devices.
In addition, the FDA regularly disseminates guidelines and guidances that provide
greater detail on a given topic and reflects the FDA’s current thinking on that topic.
These documents are drafted by the FDA and are open for review before finalization. The corresponding subject matter experts from the industry and academia provide their scientific input for consideration by the FDA. The acceptance of their
comments and suggestions is completely at the discretion of the FDA.
Since most drugs are developed with the intention of marketing them worldwide,
not just in the United States, the International Conference on Harmonization (ICH)
of Technical Requirements for Registration of Pharmaceuticals for Human Use was
established in 1990. The conference members are regulatory and pharmaceutical
industry representatives from the European Union, United States, and Japan, the
major pharmaceutical powers at that time. The main purpose of ICH was to harmonize the requirements that a sponsor will need to fulfill in order to get product
approval in major markets around the world. The harmonization is achieved by issuing guidelines which have been accepted as law in several countries but are only
used as guidances in the United States. A secondary purpose of this harmonization
is to help reduce the cost and time of research and development by avoiding the
need for sponsors to repeat many time-consuming and expensive studies to meet
country specific requirements and also significantly reduce the use of animals by
avoiding study repetition without compromising the quality, safety, and efficacy of
the final product.
Even though United States, the European Union, and Japan are the major pharmaceutical markets in the world, emerging markets are becoming significantly
important in today’s world. These include Brazil, Russia, India, and China (BRIC)
and other countries such as Mexico, Taiwan, South Africa, Poland, etc. The BRIC
countries contribute more than 40% of the current world population and occupy
more than 25% of the world’s land area. The regulatory systems for pharmaceutical
product approval in some of these countries are not yet well developed. However,
these countries provide a large customer base as well as a significant subject population for clinical trial enrollment with the following key advantages:
1. Faster enrollment of subjects into clinical trials which results in significant time
and cost savings for the sponsor.
2. Lower cost of operations.
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3. Enrollment of local subjects in clinical trials making it easier for future marketing
of the drug in that region.
For these reasons, many sponsors prefer to include Ex-US sites in their clinical
trials. However, including these Ex-US sites in the clinical trials requires knowledge
about the regulatory environment in those countries and a good understanding of the
regulatory requirements, obligations, and process of interacting with the local health
agency. Additionally, the sponsor also needs to take into account the operational
challenges that it may encounter in some of these countries. Some of these challenges include:
1. Lack of access to experienced and well-trained physicians.
2. Longer regulatory review timelines in certain countries.
3. Requirement that the regulatory filing be done in local language – giving rise to
the need for translation.
4. Lack of harmonized clinical trial requirements, processes, and reporting rules.
In most cases, the advantages far outweigh the challenges making inclusion of
these Ex-US sites in the clinical trials a very appealing proposition. A description of
the regulatory environment of individual countries is beyond the scope of this
chapter and the reader is encouraged to visit the individual countries health agency
website to obtain the appropriate information. We will use the United States as a
template for further discussion. It is important to note, however, that in most countries, the quality and nonclinical study requirements will be quite similar to those in
the United States. The process of obtaining approval to start the clinical trials, the
review timelines, clinical study conduct and documentation, and interactions with
the health agency will differ from country to country.
In the United States, an Investigational New Drug Application (IND) needs to be
filed with the FDA in order to begin Phase I clinical trials to evaluate the safety and
tolerance of the drug in healthy volunteers. The IND contains all the quality and
nonclinical information required to support Phase I clinical testing. Additionally, it
also contains all the details of the clinical study protocol and information on the
qualification of clinical investigators. The nonclinical information is typically
obtained in two species (rodent and nonrodent) using the intended route of administration and should justify the dose selection in Phase I trials. Following the acceptance of the IND by the FDA, there is a 30-day review period after which the sponsor
can proceed with the Phase I study provided the FDA does not raise any potential
issues or respond to the IND with a “clinical hold.” Subsequent to the successful
completion of Phase I clinical trials, the sponsor will start Phase II clinical trials,
with the approval of the FDA. Unlike, Phase I clinical trials, Phase II clinical trials
are conducted in the intended patient population and will evaluate the therapeutic
efficacy, dose–efficacy relationships, Pharmacokinetics and Drug Metabolism
(PKDM), and safety in the patient population. Phase II clinical trials typically
involve a moderately high number of patients and run for durations that are longer
than Phase I clinical trials. Additional quality and nonclinical data to support the
longer duration are submitted to the agency as IND amendments prior to start of
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