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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5320_Библиотеки_им_академика_М_И_Перельмана
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FIGURE 2.3 Number of compounds proceeding through various stages of drug development— an upright funnel (a), and
the steps where regulatory review and/ or approval are required in the United States, such as the investigational new drug
(IND) application submission before initiating phase I studies, a pre- NDA meeting with the FDA after the phase II studies,
and new drug application (NDA) submission for drug approval for marketing after the completion of phase III studies. (With
kind permission from Springer Science+ Business Media: Narang A.S., and Desai, D.S. (2009) Pharmaceutical perspectives
of cancer therapeutics. In Anticancer Drug Development
Pharmaceutical Dosage Forms and Drug Delivery
These stages are bounded by distinct boundaries, where the governance leadership of an organization
must make a decision whether to continue to invest in a molecule or not. These are called decision- points
or stage- gate checkpoints. At these points, interdisciplinary discussions that include both technical (e.g.,
developability risk) and nontechnical (e.g., commercial potential and competition) aspects identify risk-
reward balance and the path to commercialization of an asset, which feeds into governance decision for
a given asset or a set of assets.
2.2.1 Preclinical Development
Preclinical development involves in- depth characterization of a few select potential drug candidates,
chemical characterization of the compound and animal studies. This stage has the objectives of identifying developability and clinical risks to the compound and identifying a viable development path to a
commercial drug product. In addition, a critical decision on the starting human dose is made based on the
animal studies carried out during the preclinical phase.
2.2.1.1 Physicochemical Characterization
form stability, excipient compatibility, dissolution rate, photostability, supersaturation on pH transfer, and
studies, toxicological assessments, and phase I clinical studies. The ability to produce a commercially
viable dosage form of the compound is assessed at this stage.
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Drug Development
2.2.1.2 Efficacy Studies
27
A key goal of preclinical testing is to determine whether a compound exhibits a pharmacological activity
and is reasonably safe for initial testing in humans. After identifying some lead compounds, the pharmacological and toxicological effects of these compounds are determined. These tests involve the use of
laboratory animals, cell cultures, enzymes, and receptors, as well as computer models. For example,
animal testing may be carried out in transgenic mice or other animals that exhibit the pharmacology of a
2.2.1.3 Toxicology Studies
Animal toxicology assessment is carried out in at least two different animal species. These toxicology
studies are intended to assess the organs or organ systems in which a particular compound tends to exhibit
toxicity, as well as to identify the doses at which the toxicity appears. These animal studies are used to
and determine how quickly the drug is excreted from the body. Pharmacokinetic and pharmacodynamic
studies are conducted to analyze the absorption, distribution, metabolism, excretion, and toxicological
effects of the drug, commonly known as ADME/ Tox prediction.
Animal doses are translated into the FIH dose with normalization based on body weight or surface
area. Interspecies dose scaling for small- molecule compounds is generally carried out using body weight
logic compounds, for example, therapeutic proteins and antibodies, is generally dose per unit body surface area (e.g., mg dose per m2). The FIH doses are typically a fraction of the lowest toxic dose observed
in any animal species.
2.2.2 Clinical Development
Clinical development can be divided into four phases: Phase I, II, III, and IV, with a progressively
increasing number of subjects exposed to the drug. Such division, through distinct clinical protocols, is
intended to utilize the results of the previous phase or subphase of the study to inform the design of the
next phase of the study.
exposure relationships, and drug pharmacokinetics in a small group of healthy or patient volunteers.
III trials. Phase III trials are the clinical studies in a large group of patients. These studies are often also
called registrational clinical trials, since the results of these studies are submitted (registered) to the FDA
as a new drug application (NDA) or a biologics license application (BLA) to gain regulatory approval for
commercialization of a new drug. Phase IV studies are post- approval clinical studies that might include
The FIH clinical studies, also called phase I studies, are typically carried out in a very small cohort of
human subjects, often normal healthy volunteers. These studies are intended to assess the safety of the
compound. The drug is administered at very low doses, based on the observations in animal studies. The
doses are systematically increased in single- or multiple- dose studies under close clinical observations
to identify potential adverse events, monitor drug pharmacokinetics and biochemical markers for those
adverse events, assess target engagement, and identify doses that may be utilized in subsequent largerscale phase II and phase III studies.
The large late- stage clinical studies that form the basis of a drug’s approval are considered registrational.
human administration. Phase II studies may involve patients and are utilized to identify adverse events
phase III studies often involve comparison against a placebo or current standard- of- care treatment. This
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Pharmaceutical Dosage Forms and Drug Delivery
may vary depending on the therapeutic category and indication of the drug. For example, studies with
cytotoxic anticancer drugs are not carried out in healthy volunteers, and a placebo may not be used as a
comparator for patients with serious diseases. Increasingly, the demarcation between different phases of
to nonregistrational dose- escalation and registrational studies.
In addition, several smaller, focused clinical studies are carried out at different points in time
during drug development to support a drug product’s labeling and interchangeability. For example,
bioequivalence studies may be carried out to bridge a phase I formulation with a phase III formulation or
to support a formulation change during clinical development. Examples of other focused studies include
compromised patients.
The larger- scale studies are carried out in an increasing number of subjects (Figure 2.3). As clinical
trials progress, the dose and dosing regimen are optimized to the effective levels that present an accept-
(such as the dose and frequency of administration), these studies seek to differentiate the new drug candidate from the existing therapeutic options for a given set of patients. Thus, studies may be carried out to
Phase IV studies involve post- commercialization monitoring of drug effects. They are designed to
monitor a drug’s long- term safety and effectiveness, as well as to uncover any rare but serious side effects
that may not have been evident in earlier, relatively smaller pools of healthy and patient volunteer studies.
In addition, studies may be carried out in special patient populations— such as pediatrics, geriatrics, and
populations.
2.2.2.1 Phase I Clinical Trials
studies are closely monitored and may be conducted in patients (when ethically required, e.g., anticancer
drugs), but are usually conducted in healthy subjects. Phase I clinical trials are relatively short (several
-
cologic effects. Thus, these studies often involve dose escalation within a clinical trial.
These studies also involve measurement of plasma drug concentration to determine how a drug is
absorbed, distributed, metabolized, and excreted (ADME), as well as the duration of its action. Information
for the next phase of clinical trials.
2.2.2.2 Phase II Clinical Trials
Once an experimental drug has proven safe and well tolerated in phase I healthy volunteer studies, it
This testing phase also helps determine the common short- term side effects and risks associated with
the drug.
Two key aspects of late- stage clinical development are (1) randomization and (2) blinding.
• Randomization
group of patients receives the experimental drug, while a second control group receives the
treatment that represents a current standard of care, or placebo. Placement of the subject into the
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drug treatment or control group is done by random assignment. The randomization of subject
assignment is an important statistical control to obviate any bias in study design.
• Blinding: An important methodology to avoid any bias during clinical testing in terms of patient
perception and response is for the patient to not know whether he or she is receiving the drug or the
control option. A single- blind study is a clinical study in which the patient does not know the therapy,
but the healthcare providers, including the physician, may know what is being administered.
However, the clinical studies are often double- blinded
knows which patients are getting the experimental drug. A double- blinding approach overcomes bias in
ence. The drug product manufacturer often carries out double-blinding by providing two look- alike medicinal products that are only coded differently. In certain cases, the blinding may be carried out by the
on- site healthcare professional, such as the pharmacist, who prepares drug products for administration
and prepares the blinded labels.
Phase II studies are designed to determine the correct dose and, thus, are often referred to as dose-
2.2.2.3 Phase III Clinical Trials
indications, determine whether the drug produces a broader range of adverse effects than those exhibited
in the small study populations of phase I and II studies, and identify the best way of administrating and
using the drug for the purpose intended. Phase III studies also provide an adequate basis for extrapolating
the results to the general population and transmitting that information in the physician labeling.
2.2.2.4 Evolving Clinical Development Paradigms
In cases where phase I studies involve patients and are adequately extensive and detailed, phase II
studies may be bypassed. Similarly, in cases where phase II studies are extensive, they may be used as
registrational studies, thus bypassing the need for phase III studies. Such decisions are made on a case-
candidate.
As mentioned earlier, the division of clinical studies into distinct phases is based on the generation of
distinct clinical protocols, with an intention to utilize the results of the previous phase or subphase of the
study to inform the design of the next phase of the study. In cases where the decision tree for how the
seamless. Such clinical studies continue the treatment of a selected cohort of patients enrolled in a phase
II study into the extended phase III study, while enrolling additional patients to meet the requirements of
the number of subjects needed for the phase III study.
In addition, clinical study designs can be adaptive. Adaptive clinical trial designs allow changes in the
design or analyses while the study is in progress. These changes are guided by the accumulated data at an
duration or the number of subjects required for the study.
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2.3 Pharmaceutical Development
Pharmaceutical Dosage Forms and Drug Delivery
Pharmaceutical development provides the drug product needed for preclinical and clinical studies to identify
the biological mechanism of a new drug and its clinical utility. In designing the drug product, functions of
discovery and development to provide stage- appropriate drug products for preclinical and clinical testing, to
bridge the studies carried out at different stages of development, and to enable commercialization of a product
and process that ensures reproducible manufacture of a high- quality drug product.
Pharmaceutical scientists work on developing suitable dosage forms for drug administration at different
stages of drug development. These might include, for example, a parenteral solution formulation during
in vitro and animal models. During phase I studies, the formulation could
be a suspension, drug- in- capsule (DIC), or drug- in- bottle (DIB) formulation. A more representative tablet
dosing and commercialization.
In designing the drug product, pharmaceutical development considerations include the target population (children or adults), the amount of drug to be given in each dose, storage stability of the drug product,
the characteristics of the drug and disease state, the preferred route of administration, drug stability, and
robustness of the manufacturing process. An early assessment of the properties of the desired dosage
form can contribute greatly to the speed of the drug development process.
2.3.1 Preformulation and Formulation Studies
Preformulation
formulation studies to develop the initial features of the proposed pharmaceutical product or dosage form
formulation includes substances called excipients in addition to the active pharmaceutical ingredient (API).
Preformulation and formulation studies take approximately 3 years concurrently with preclinical (animal)
-
tration of the drug. The initial formulations prepared for phases I and II of the clinical trials should be of high
Three key goals of pharmaceutical development are to ensure the delivery of stage- appropriate drug
products with acceptable (a) stability, (b) bioavailability, and (c) manufacturability.
2.3.2 Stage- Appropriate Drug Product Design
The drug product used for testing at earlier stages of development, such as preclinical or phase I, is
generally different from those used at later stages. Stage- appropriate drug product design considers the
objectives and requirements for each stage. For example, during animal toxicology studies, the objective
is primarily to maximize exposure and allow the administration of large doses. At this stage of development, storage stability requirements are minimal, and the drug product can be handled in a carefully
controlled manner in the laboratory setting. Therefore, a high- concentration solution dosage form may be
preferred at this stage of development. The objective in the later stages of development, such as phases
market- image formulation is generally developed for those later stages of development.
2.3.3 Stability
A drug product is expected to maintain the chemical purity (i.e., chemically unchanged API) and physical
integrity (e.g., the same polymorphic form) of the drug, the physical integrity of the dosage form (e.g., no
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breakage of tablets), and reproducible drug release from the dosage form throughout the projected storage
period under recommended storage conditions.
The stability requirements for drug products are different at each stage of drug development and
depend primarily on the anticipated duration of storage and the storage conditions (e.g., refrigerated or
room temperature) for animal and human studies. For commercialization, the stability requirements are
based on the target shelf life at the desired FDA- approved label storage conditions. Generally, no less
than 18 months of shelf life is considered commercially viable.
Harmonization of stability requirements across the companies involved in new drug development for
product commercialization across different regions of the world is carried out through the guidelines
conditions that can be considered representative of year- round weather in different regions of the world.
For example, normal room temperature storage conditions for the United States and Western Europe have
2.3.4 Bioavailability
A vital aspect of any dosage form is to be consistent (dose- to- dose and batch- to- batch) in delivering the
total amount of drug into the systemic circulation and the rate at which it is delivered (bioavailability)
from the drug product. Optimization and control of drug product properties that ensure robust manufacturing, physicochemical stability, and reproducible drug release help ensure consistent bioavailability.
the mechanistic basis of their impact is studied. In vitro assays are developed to measure drug release,
and their results are correlated with in vivo performance. Such a correlation between in vitro and in vivo
performance is termed in vitroin vivo correlation (IVIVC).
In silico modeling of drug absorption is commonly used to understand and predict a drug’s behavior
after administration. These models are a complex array of equations that are solved simultaneously
using computing software, such as the commercially available GastroPlus® or Simcyp®, to identify
pharmacokinetic properties (e.g., ADME rates) as an outcome of the drug (e.g., solubility), dosage form
(e.g., dissolution rate), mode of administration, and species characteristics.
In addition to achieving reproducible bioavailability of a given dosage form, pharmaceutical scientists
pay attention to changes in bioavailability through different phases of drug development due to changes
in animal species (e.g., bioavailability differs among rats, dogs, monkeys, and humans, even with the
same dosage form, due to differences in physiology), translation of animal data into humans (e.g., solution administration to animals by IV route vs. oral solid dosage form for human administration), changes
in dosage form (e.g., capsules in phase I vs. tablets in phase II), changes in human patient populations
(e.g., normal healthy volunteers vs. patients suffering from a chronic disease state such as renal impairment), or other factors of human drug administration (e.g., bioavailability in the fasting state can be
different from that in the fed state and special patient populations, such as pediatric and geriatric patients).
Extensive dosage form characterization and bridging studies (e.g., relative bioavailability of two different
2.3.5 Manufacturability
quality attributes in a robust manner at a stage- appropriate scale of manufacture is critical to ensuring that
consistent dosage form is used throughout development. For drug products in late- stage development,
such as phase III clinical trials, and in preparation for commercialization, in- depth investigations are
carried out to understand and carefully control the incoming raw materials, manufacturing process, and
the quality of the output drug substance or drug product through well- designed mechanistic and statistically controlled design- of- experiment (DoE) studies.
can impact the patient, such as delivered dose uniformity or the content of impurities. Critical material
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Pharmaceutical Dosage Forms and Drug Delivery
attributes (CMAs) of incoming raw materials, such as excipients, are delineated. These are the physico-
2.4 Regulatory Approval
Regulation and control of new drugs in the United States are the responsibilities of the federal FDA
(www.fda.gov). The FDA regulates the following:
•
and approval of an IND.
• Marketing of a new drug product or an existing drug product for a new application by requiring the
The agency, a frequently used synonym for the FDA, has various constituent centers, including the
Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research
(CDER), the Center for Devices and Radiological Health (CDRH), and the Center for Food Safety and
Applied Nutrition (CFSAN). The CDER evaluates prescription, generic, and OTC drug products for safety
they are in the market. The CBER regulates biologics not reviewed by the CDER, such as vaccines, blood
and blood products, gene therapy products, and cellular and tissue transplants. Many biopharmaceuticals
is responsible for monitoring sites and facilities where pharmaceuticals are manufactured. The FDA has
the authority to enforce withdrawal or recall of those drug products from the market that do not meet
A typical process for the discovery and commercialization of new drug products in the United States
generally follows the following pathway:
• Preclinical laboratory tests and in vivo preclinical studies in animals.
• Submission of an IND application to the FDA for clinical testing.
•
• Submission of an NDA to the FDA for a BLA.
• Approval of the NDA or BLA by the FDA before any commercial sale.
2.4.1 Investigational New Drug Application
After completing preclinical testing, the sponsor of a potential NDA/ BLA makes the decision about
whether or not the drug has enough potential to proceed to in vivo studies in humans. To initiate the clin-
components, including the CMC of the test article or drug product, clinical study plan, and investigator’s
The IB is the document that the sponsor of the clinical study provides to the physician and healthcare
professionals to successfully execute the clinical study. In addition to gaining the FDA’s approval for the
IND, the IB must also be reviewed and approved by the institutional review board (IRB) of each clinical
site (e.g., a hospital and medical center) where the proposed clinical trials will be conducted. Once an
considered approved if the FDA does not get back to the sponsor within that time.
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2.4.2 New Drug Application
33
After successful completion of phase I through phase III clinical development, a drug’s sponsor submits
the results of all the studies to the FDA in an NDA to obtain approval for marketing of the new drug.
The NDA is a formal request to the FDA to approve a new drug product for sale and marketing in the
United States. Technically, the FDA regulates interstate transport of medicinal products, which is what it
approves. Each state has its own regulatory body for new drug products that can be marketed within its
FDA is considered a benchmark for the ability to market a new drug in all states.
2.4.2.1 Basis of Approval
The NDAs are usually comprehensive documents that detail all studies carried out and can run over
human clinical trials of an IND become part of the NDA. The goals of the NDA are to provide enough
information to permit the FDA reviewers to reach the following key conclusions:
•
outweigh the risks.
• Whether the drug’s proposed labeling is appropriate and what it should contain.
• Whether the methods used in manufacturing the drug and the controls used to ensure the drug’s
quality are adequate to preserve the drug’s identity, strength, quality, and purity.
2.4.2.2 Role of Advisory Committees
The FDA often constitutes advisory committees consisting of experts in respective areas in several dis-
Committees are typically asked to comment on whether the approval, clearance, or licensing of a medical
product for marketing is supported by adequate data. The primary role of an advisory committee is to
provide independent advice that will contribute to the quality of the agency’s regulatory decision- making
and lend credibility to the drug product review process. In this way, the FDA can make sound decisions
about new medical products and other public health issues.
Although advisory committees have a prominent role in the approval of new drug products, they
may also be called in earlier in the product development cycle or asked to consider issues relating to
products that are already in the market. Committees are typically asked to comment on whether the submitted data adequately supports the approval, clearance, or licensing of a medical product for marketing.
Advisory committees may also recommend that the FDA request additional studies or suggest changes
to a product’s labeling. Their recommendations are nonbinding advice to the agency. While committee
agency.
2.4.3 Biologics License Application
A BLA is an application for marketing authorization of a biological drug product, such as proteins, antitorically unique not only in their origin but also in their physicochemical characteristics and the extent of
characterization that is contemporarily possible. For example, while the small- molecule drugs are well
characterized to an atomic level, with crystal structures of crystalline drugs are elucidated. However,
the large- molecule compounds are generally non- crystalline and are challenging to isolate in solid
exact characterization of each atom and bond is currently not possible. Thus, while the impurities of
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small- molecule compounds are known and characterized to exact molecular structure, the structural
variants of large- molecule compounds are generally characterized only as size or charge variants.
Accordingly, the criteria for comparability of different drug substance and drug product batches,
product scale- up and manufacturing control, scaling of dose across species, and analytical characteriza-
products. However, the drug development process remains the same for small- and large- drug molecules,
and different experts within the FDA review BLA and NDA.
2.4.4 Abbreviated New Drug Application
An abbreviated NDA (ANDA) is used to gain approval for a generic equivalent of a drug product that is
already approved and is being marketed by the pioneer or original sponsor of the drug. Generic drugs are
and intended for administration by the same route. Generic drug products may have different inactive
ingredients and/ or product- manufacturing processes and controls.
Generic products offer low- cost alternatives to branded medicines once the patent life of the molecule expires. The underlying precept in the approval of generic drug products is that drug products with
parameters include area under the curve (AUC) and maximum plasma concentration (Cmax). Therefore,
the branded or innovator drug product. The CMC requirements for generic drug products do not change.
2.4.5 Biosimilars
Biosimilars are the generic equivalents of biological drug products. Often called follow- on biologics, the
equivalence requirements for generic biologics are still evolving. The clinical proof of equivalency for
biosimilar drug products to branded drugs are considered. These may include, for example, a combination of a relative proportion of size and charge variants in the molecule.
2.4.6 Approval and Post- Marketing Surveillance
Once the FDA approves an NDA or a BLA, the drug’s sponsor can sell the new medicine to the public
in the United States. Approval of the FDA for marketing a new drug product does not end a sponsor’s
responsibility toward the clinical investigation of the drug. Continued clinical investigation, often called
phase IV studies, may contribute to understanding the drug’s mechanism or scope of action, indicate possible new therapeutic uses, and/ or investigate the need for additional dosage strengths, dosage forms, or
routes of administration. Phase IV monitoring in commercial use may also reveal additional side effects,
especially rare events that may not be detected even in large- scale clinical trials.
The sponsor is required to submit periodic reports to the FDA, including any adverse event reports,
internal quality investigations, and/ or changes to manufacturing and controls since the NDA’s approval.
more of the following actions: Labeling changes, boxed warnings, product withdrawals, and medical and
safety alerts.
2.4.7 Accelerated Development/ Review
Accelerated development/ review is a specialized mechanism for speeding up the development of drugs
no therapy exists. This process incorporates several elements, such as abbreviated clinical studies, to
accelerate drug development. Safeguards to protect the patients and the integrity of the regulatory process balance regulatory review. The fundamental element of this process is that the manufacturers must
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2.5 Post- Commercialization Activities
35
Commercialization of a drug product involves many different functions in addition to research and devel-
goods analyses and the feasibility of a particular product and technology. The manufacturing function is
responsible for day-to-day operations to produce the drug product reproducibly to meet market demand.
The post- commercialization involvement of R&D with a particular drug molecule focuses on three
areas: Manufacturing support, intellectual property, and life cycle management.
2.5.1 Manufacturing Support
As the manufacturing operations produce multiple batches, they may face unforeseen problems that
require R&D input and troubleshooting. These problems often come from changes in the input raw
common problems, the ones requiring additional research are usually brought to the interface with
or CPPs.
The regulatory bodies restrict post- approval changes to drug substances or products or their manufacturing process. Thus, an NDA or BLA sponsor is required to manufacture the drug product within the
post- approval, depending on the nature and extent of the change and its impact on the drug product. In
that case, the sponsor must seek the FDA’s approval before implementing this change in commercial
operations.
2.5.2 Intellectual Property
incentive to encourage individuals and organizations to invest in developing new medicines for unmet
medical needs.
When entering the development pipeline, a new compound is patented by the innovator company.
A typical patent life consists of the discovery and development of the compound through various stages
of clinical trials. On commercialization, the patent provides exclusive marketing rights to the sponsor
and allows the sponsor to recoup the cost of developing the drug. The commercial return on investment
innovator company is under constant pressure to continue discovering and developing new medicines to
replace the ones that would predictably expire at the end of their patent life.
of life cycle management.
2.5.3 Life Cycle Management
The typical life cycle of an NCE/ NME is several decades, with different stages that can generally be
characterized as follows:
•
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