Initiation of new clinical trials and clinical trials with new drug candidates by requiring the filing and approval of an IND.
Regulatory
approval
Regulation
and control of new drugs in the United States are the respon-sibilities of the
federal FDA (http://www.fda.gov). The FDA regulates
the following:
·
Initiation of new clinical trials and clinical trials with
new drug candidates by requiring the filing and approval of an IND.
·
Marketing of a new drug product or an existing drug product
for a new application by requiring the filing and approval of an NDA or a BLA.
The
agency, a frequently used synonym for the FDA, has various constit-uent
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 pre-scription, generic, and OTC drug
products for safety and efficacy before they can be marketed. It also monitors
all human drugs and biophar-maceuticals once 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
bio-pharmaceuticals fall under the responsibilities of both the CBER and the
CDER. The Office of Regulatory Affairs (ORA) is responsible for moni-toring
sites and facilities in which pharmaceuticals are manufactured. The FDA has the
authority to enforce withdrawal or recall of those drug products from the
market that do not meet quality, safety, and efficacy requirements.
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.
·
Clinical trials for establishing product safety and
efficacy.
·
Submission of an NDA to the FDA for a BLA.
·
Approval of the NDA or BLA by the FDA before any commercial
sale.
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
clinical study, the sponsor needs to file an IND application with the agency.
An IND appli-cation has several components, including chemistry, manufacturing,
and control (CMC) of the test article or drug product, clinical study plan, and
investigator’s brochure (IB). The IND application presents results of previ-ous
experiments; how, where, and by whom the new studies will be con-ducted; the
chemical structure of the compound; its mechanism of action in the body; any
toxic effects found in animal studies; and how the compound is manufactured.
The
IB is the document that the sponsor of the clinical study provides to the
physician and healthcare professionals to successfully execute the clini-cal
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 IND application is filed, the FDA has 30 days
to respond to this initial admission. The IND application is considered
approved if the FDA does not get back to the sponsor within that time.
After
successful completion of phase I through phase III clinical development, a
drug’s sponsor submits the result 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 inter-state 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 territory. Usually, the
regulations of each state reflect that of the U.S. FDA. Therefore, approval of
the FDA is considered a benchmark for the ability to market a new drug in all
states.
The
NDAs are usually comprehensive documents that detail all studies carried out
and can run over 100,000 pages in print; however, recent electronic submissions
have eliminated the need for printing. The average NDA review time for NMEs
approved in 2016 was 10.1 months. The NDA must contain all of the scientific
information that the company has gathered. The data gathered during the animal studies
and human clinical trials of an IND become the 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:
·
Whether the drug is safe and effective for its proposed
use(s), and whether the benefits of the drug 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
con-trols used to ensure the drug’s quality are adequate to preserve the drug’s
identity, strength, quality, and purity.
The
FDA often constitutes advisory committees consisting of experts in respective
areas in several disciplines, such as clinical practitioners in a spe-cific disease
area, to assist in the review of an NDA. Committees are typically asked to
comment on whether the approval, clearance, or licensing of a medi-cal 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 support
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 discussions and final votes are very
important to the FDA, the final regulatory decision rests with the agency.
A
BLA is an application for marketing authorization of a biologic drug product,
such as proteins, antibodies, antibody–drug conjugates, vaccines, and gene and
cell therapy products. These products are historically unique not only in their
origin but also in the physicochemical characteristics and the extent of
characterization contemporarily possible. For example, while the small-molecule
drugs are well characterized to an atomic level, with crystal structures of
crystalline drugs elucidated, the large-molecule compounds are generally not
crystalline and are difficult to isolate in solid state as pure compounds. In
their solution state, they are quite big (moluecular weight >10 kDa) and
exact characterization of each atom and bond is currently not possible. Thus,
while the impurities of small-molecule compounds are known and characterized to
exact molecular structure, the structural variants of large-molecule compounds
are generally character-ized 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 characterization of drug sub-stances and drug product
differ significantly between the small- and large-molecule drug products.
Although the process of drug development remains the same for both small- and
large drug molecules, different experts within the FDA review BLA and NDA.
An
abbreviated NDA (ANDA) is used to gain approval for a generic equiva-lent of a
drug product that is already approved and is being marketed by the pioneer or
original sponsor of the drug. Generic drugs are defined as prod-ucts containing
the same active ingredient as the branded drug, in the same dosage form, and
intended for administration by the same route. Generic drug products may have
different inactive ingredients and/or product-manufacturing process 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 similar drug pharmacokinetics will have
similar efficacy and toxicity profile. These pharmacokinetic parameters include
area under the curve (AUC) and max-imum plasma concentration (Cmax). Therefore,
clinical safety and efficacy testing for generic drug products are waived on
the basis of their bioequiva-lence to the branded or innovator drug product.
The CMC requirements for the generic drug products do not change.
Biosimilars
are the generic equivalents of biologic drug products. Often called follow-on
biologics, the equivalence requirements for generic bio-logics are still
evolving. The clinical proof of equivalency for biosimilars currently involves
abbreviated safety and efficacy studies. In addition, simi-larity criteria for
biosimilar drug products to branded drugs are considered. These may include,
for example, a combination of relatively proportion of size and charge variants
in the molecule.
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 of a new
drug product does not end a sponsor’s responsibility toward clinical
investigation of the drug. Continued clinical investigation, often called phase
IV studies, may contribute to the understanding of 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 the 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. If an adverse effect is
identified with a marketed drug, the Office of Drug Safety (ODS) can take one
or more of the following actions: labeling changes, boxed warn-ings, product
withdrawals, and medical and safety alerts.
Accelerated
development/review is a specialized mechanism for speeding up the development
of drugs that promise significant benefit over the exist-ing therapy for
serious or life-threatening diseases for which no therapy exists. This process
incorporates several elements, such as abbreviated clin-ical studies, aimed at
accelerating 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 continue to test after
approval to demonstrate that the drug indeed provides therapeutic benefit to
the patient.
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