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Transcript of New Drug Application Hardcopy
ABSTRACT
The NDA is a vehicle seeking approval to the new product after the completion of
carefully design preclinical and clinical studies. The FDA’s approval of an NDA indicates that
the body of scientific evidence submitted sufficiently demonstrating the drug or the drug
products safety efficacy for the proposed chemical indications showing adequate assurance of its
proper manufacture control and final labelling and accurately necessary information for its
proper use.
An Abbreviated New Drug Application (ANDA) is an application for generic drug
approval for an existing licensed medication or approved drug. It provides documentation on
chemistry manufacturing controls, bioavailability of the proposed product to demonstrate
biological equivalency to the product.
NEW DRUG
• A combination of two or more old drugs or a change in the usual proportions of drugs in
an established combinations product is considered new if the change introduces a
question of safety or efficacy.
• According to FDA, a new drug is any that is not recognized as being safe and effective
in the conditions recommended for it use among experts who are qualified by scientific
training and experience.
• A proposed new use for an established drug, a new dosage schedule of regimen , a new
route of administration, or a new dosage form all cause a drug or drug products status to
new and triggers reconsideration for safety and efficacy
• A change in a previously approved drug products formulation or method of manufacture
constitutes newness under the law.
NEW DRUG DEVELOPMENT PROCESS
• New chemical entity
• Pre clinical studies
• Investigational new drug application(IND)
• Clinical trials
• New drug application.
• Post marketing surveillance
Investigational New Drug Application (INDA):
Current Federal law requires that a drug be the subject of an
approved marketing application before it is transported or distributed across state lines. Because
a sponsor will probably want to ship the investigational drug to clinical investigators in many
states, it must seek an exemption from that legal requirement. The IND is the means through
which the sponsor technically obtains this exemption from the FDA.
During a new drug's early preclinical development, the
sponsor's primary goal is to determine if the product is reasonably safe for initial use in humans,
and if the compound exhibits pharmacological activity that justifies commercial development.
When a product is identified as a viable candidate for further development, the sponsor then
focuses on collecting the data and information necessary to establish that the product will not
expose humans to unreasonable risks when used in limited, early-stage clinical studies.
FDA's role in the development of a new drug begins when the
drug's sponsor (usually the manufacturer or potential marketer) having screened the new
molecule for pharmacological activity and acute toxicity potential in animals, wants to test its
diagnostic or therapeutic potential in humans. At that point, the molecule changes in legal status
under the Federal Food, Drug, and Cosmetic Act and becomes a new drug subject to specific
requirements of the drug regulatory system.
There are three IND types:
An Investigator IND is submitted by a physician who both initiates and conducts an
investigation, and under whose immediate direction the investigational drug is
administered or dispensed. A physician might submit a research IND to propose studying
an unapproved drug, or an approved product for a new indication or in a new patient
population.
Emergency Use IND allows the FDA to authorize use of an experimental drug in an
emergency situation that does not allow time for submission of an IND in accordance
with 21CFR , Sec. 312.23 or Sec. 312.34. It is also used for patients who do not meet
the criteria of an existing study protocol, or if an approved study protocol does not exist.
Treatment IND is submitted for experimental drugs showing promise in clinical testing
for serious or immediately life-threatening conditions while the final clinical work is
conducted and the FDA review takes place.
There are two IND categories:
Commercial
Research (non-commercial)
The IND application must contain information in three broad areas:
Animal Pharmacology and Toxicology Studies - Preclinical data to permit an assessment
as to whether the product is reasonably safe for initial testing in humans. Also included
are any previous experience with the drug in humans (often foreign use).
Manufacturing Information - Information pertaining to the composition, manufacturer,
stability, and controls used for manufacturing the drug substance and the drug product.
This information is assessed to ensure that the company can adequately produce and
supply consistent batches of the drug.
Clinical Protocols and Investigator Information - Detailed protocols for proposed clinical
studies to assess whether the initial-phase trials will expose subjects to unnecessary risks.
Also, information on the qualifications of clinical investigators--professionals (generally
physicians) who oversee the administration of the experimental compound--to assess
whether they are qualified to fulfill their clinical trial duties. Finally, commitments to
obtain informed consent from the research subjects, to obtain review of the study by an
institutional review board (IRB), and to adhere to the investigational new drug
regulations.
CONTENT OF THE IND:
The content of the IND is as specified in the code of federal regulations and is submitted under a
cover sheet (form FDA-1571).
Requirements:
• Sponsor’s information.
• Investigation monitors information.
• Review evaluation body information.
• Contract research organization.
• Phase identity.
• Introductory statement and general investigation plan.
• Description of investigational plan.
• History of previous human experience.
• Chemistry, manufacture and control information
• Pharmacology and toxicology information.
• Previously investigated drug information component.
• Clinical protocol.
• Commitment.
• Investigator brochure.
• Commitment undertaking.
PRE IND MEETINGS:
On request FDA will advice sponsors on scientific technical of formatting concerns
Relating to the preparation and submission of IND.
It includes
• Advice on adequacy of data to support an investigational plan.
• Design of clinical trial.
• Filing of NDA.
FLOW CHART:
New Drug Application (N D A):
Introduction:
Introduction The new drug application (N D A) is a critical component in the drug
approval process. The NDA contains Clinical and non clinical test data and analyses, Drug
chemistry information, and Descriptions of manufacturing procedures. An NDA consists of
thousands of pages of information to be reviewed by FDA teams composed of highly qualified
individuals with expertise in their respective technical fields.
Usually, six different teams are responsible for reviewing an NDA. The teams are
organized by technical reviewing responsibilities: Clinical Pharmacology/toxicology Chemistry
Statistics Biopharmaceutical and Microbiology. Introduction
The FDA has established guidelines for formatting, assembling, and submitting the
NDA. Failure to follow these guidelines can result in deficiencies that could Delay review,
require an amended application, or Result in a refusal to File. Introduction
Most of the FDA guidelines regarding NDAs were written and implemented in
early 1987. NDA shares many common elements with the Common Technical Document (CTD)
developed by the ICH Introduction
Assembling Applications for Submission:
Assembling Applications for Submission, the FDA requires drug
sponsors to submit multiple copies of the NDA The archival copy The review copy The field
copy In 1997 the FDA’s Center for Drug Evaluation and Research (CDER) published guidelines
that allow sponsors to submit NDAs electronically instead of on paper.
The Archival Copy:
The Archival Copy Contains all sections of the NDA, including The
cover letter, Form FDA-356h (Application to Market a New Drug, Biologic, or an Antibiotic for
Human Use), The administrative sections, Comprehensive NDA index, and All technical
sections. It must contain four copies of the Labeling section. It must contain three additional
copies of the CMC and Methods Validation Package in a separate binder. The archival copy is
the only copy that contains the Case Report Tabulation and Case Report Forms.
The Review Copy: The Review Copy Intended for reviewers in the corresponding technical
disciplines. In addition to the appropriate technical section, each review copy also includes ,the
cover letter, Form FDA-356h, The administrative sections, Comprehensive NDA index
Individual table of contents, The Labeling section, and The Application Summary.
The Field Copy: The Field Copy required since 1993 for use by FDA inspectors during
pre approval facilities inspections. It includes the Cover letter and Form FDA-356h, the
administrative sections, the comprehensive NDA index Individual table of contents, The
Labeling section, The Application Summary, and CMC and Methods Validation Package.
NDA CONTENTS: The NDA may have as many as 20 different sections in addition to
the Form FDA-356h itself. The specific contents of the NDA will depend on the Nature of the
drug and The information available at the time of submission. The application Form FDA-356h
serves as Checklist as well as Certification that the sponsor agrees to comply with a range of
legal and regulatory requirements. NDA includes
CONTENTS:
1: Index NDA Section
2: Labeling NDA Section
3: Application Summary NDA Section
4: Chemistry, Manufacturing, and Controls (CMC) NDA Section
5: Nonclinical Pharmacology and Toxicology NDA Section
6: Human Pharmacokinetics and Bioavailability NDA Section
7: Microbiology NDA Section
8: Clinical Data NDA Section
9: Safety Update Reports.
10: Statistics NDA Section
11: Case Report Form Tabulations NDA Section
12: Case Report Forms (CRFs) NDA Section
13: Patent Information NDA Section
14: Patent Certification NDA Section
15: Establishment Description NDA Section
16: Debarment certificate NDA Section
17: Field copy certification NDA Section
18: User fee coversheet NDA Section
19: Financial Disclosure NDA Section
20: Other/ Pediatrics NDA CONTENTS
NDA Section 1: Index: The NDA index is a comprehensive table of contents that enables
the reviewers to find specific information in this massive document quickly. The NDA index
should follow immediately after the Form FDA-356h and the administrative items. It must show
the location of every section in the archival NDA by volume and by page number.
It should guide reviewers the data in the technical sections, the summary, and the supporting
documents , each separately bound technical section should also contain a copy of the overall
NDA index in addition to its own table of contents based on the index.
NDA Section 2: Labeling: The labeling section must include all draft labeling that is
intended for use on The product container, Cartons or packages, The proposed package insert.
The draft product labeling include the following sections
1. Description
2. Clinical Pharmacology
3. Indications and Usage
4. Contraindications
5. Warnings
6. Precautions
7. Adverse Reactions
8. Drug Abuse and Dependence
9. Overdosage
10. Dosage and Administration
11. How Supplied (primary and secondary packages)
NDA Section 3: Application Summary:
The application summary is an abbreviated version of the entire application. This
overview is one of the few elements of the application that all reviewers receive, and it should
give them a clear idea of the drug and its application. The summary usually comprises 50 to 200
pages
The application summary is an abbreviated version of the entire application. This
overview is one of the few elements of the application that all reviewers receive, and it should
give them a clear idea of the drug and its application. The summary usually comprises 50 to 200
pages.
Application Summary For each section of the labeling, include annotations
referring to information in the summary and technical sections of the application that support the
inclusion of each statement in the labeling with respect to Animal pharmacology and/or animal
toxicology, Clinical studies, Integrated Summary of Safety (ISS) and Integrated Summary of
Effectiveness (ISE) Safety (ISS) and Integrated Summary of Effectiveness (ISE) Pharmacologic
class Scientific rationale Intended use Potential clinical benefits Application Summary Foreign
marketing history
The summary must include a list of any countries in which the drug is or was
marketed, along with the dates when it was marketed, if they are known. It must also include a
list of any countries in which the drug has been withdrawn from marketing for any reason
relating to safety or efficacy or in which an application has been rejected.
NDA Section 4: Chemistry, Manufacturing, and Controls (CMC)
The first technical section of the NDA It includes information on The
composition, Manufacturing, and Specifications of the drug substance and the drug product. The
three main elements are Chemistry, manufacturing and controls information, Samples Methods
validation package.
The CMC information must include Description of the drug substance or active
ingredient, Its stability Physical and chemical characteristics, Provide the names/designations of
the drug substance, including: Generic/common name Chemical name (IUPAC/USAN/CAS)
Code(s) (CAS/internal)
CMC Provide a structural overview, including: Molecular structure Empirical
formula Molecular weight Elemental composition. The description of the drug substance’s
physical and chemical characteristics should include: Appearance, including color, crystalline
form, and odor Melting/boiling point Refractive index, viscosity, and specific gravity
Polymorphs, including modifications (forms) and relative kinetic/ thermodynamic stabilities
The physical and chemical characteristics should also include Solubility,
Ionization constants, and Partition coefficients at various pHs. Solubility in common organic
solvents as well as in various aqueous media Water 0.1 N HCl 0.02 N HCl SGF without pepsin
Water buffered to various acidic/neutral/basic pHs
CMC Provide a reference standard (RS) to elucidate the drug substance’s
chemical structure, including Preparation method, Test methods, Test results as shown by a
certificate of analysis (C.O.A). Provide proof that the reference standard was adequately tested
and characterize the spectra completely.
It Provides structural elucidation using a reference standard as applicable.
Measures might include X-ray (in the case of absolute configuration or polymorphism)
UV/visible spectrum FTIR spectrum 1H NMR/13C NMR spectrum Low-resolution/high-
resolution mass spectrum Elemental analysis
The CMC information must also include the Names, addresses and functions of
each site where the drug substance is manufactured or tested. The description of the drug
substance manufacturing methods must include Synthesis scheme Synthesis description Typical
executed manufacturing record Compilation of and analytical controls for starting materials;
Reagents, Solvents Catalysts, and Intermediates Suppliers for starting materials
The discussion of drug substance analytical controls should include the
following: Specifications Methods Rationale for methods/specifications Method validations
Batch analytical data (including impurity profiles cross-referenced with toxicology studies)
Sampling plan
It Provides information on drug substance stability, including:
Ambient/accelerated stability data Retest dating highly stressed (e.g., acid, base, reflux) data
Provide a listing of all inactive ingredients. For compendial (e.g., UPS/NF) inactive ingredients,
reference the appropriate current compendial monographs and provide more precise
specifications as necessary.
CMC For noncompendial ingredients that fall under 21 CFR such as D&C and
FD&C dyes, reference the appropriate section of 21 CFR and provide any additional
specifications beyond the scope of the CFR. For noncompendial items that are not regulated by
21 CFR, provide appropriate analytical specifications and methods.
It Provides information on the drug product manufacturing methods: Summary
and schematics of manufacturing procedure Master batch record for proposed marketed products,
including actual operating conditions, type and size of equipment, and in process controls and
tests Executed batch record
The section on drug product packaging must include: Summary of
container/closure system(s) Listing of packaging components and component/resin suppliers
Specifications for each packaging component DMF authorization letters Description of the
packaging process Test methods (as appropriate) Developmental data that confirms the
suitability of the packaging. This includes water vapor permeation data for plastic containers/
closures and compatibility testing for solutions, suspensions, emulsions, etc.
The drug product stability information will differ slightly from the drug
substance stability information. Unstressed/stressed stability data Statistical analysis to establish
consistency of data Expiration dating Post approval stability commitment/protocol
CMC For an NDA, provide a list of all drug product investigational
formulations used in clinical studies, along with the quantitative composition of each
formulation. Every NDA must include an environmental assessment (EA) The EA, also called
the environmental impact analysis report, includes an analysis of the manufacturing process and
ultimate use of the drug product as well as a discussion of how the process and the drug product
may affect the environment.
The final component of the CMC technical section is the methods validation
package. The package must comprise: Specifications and test methods for each component used
in the drug product Specifications and methods for the drug product Validation of test methods
Names and addresses of component suppliers Names and addresses of the suppliers of the
container closure system.
NDA Section 5: Nonclinical Pharmacology and Toxicology:
The second technical section of the NDA provides a description of all
animal and in vitro studies with the drug. Include a narrative summary of notable findings in all
studies and a discussion of notable findings across the various studies.
It provides individual study reports, including Pharmacology, Toxicology,
and ADME studies. For the pharmacology studies, following data is required 1. Effects related to
the therapeutic indication, such as the pharmacodynamic ED 50 in dose-ranging studies and the
mechanism of action (if known) 2. Secondary pharmacological actions in order of clinical
importance as possible adverse effects or as ancillary therapeutic effects 3. Interactions with
other drugs NDA Section 5: Nonclinical Pharmacology and Toxicology
The Toxicology information must include information on Acute toxicity,
Multidose toxicity (including sub chronic, chronic, and carcinogenicity) Special toxicity studies,
as well as Reproduction studies and mutagenicity studies. NDA Section 5: Nonclinical
Pharmacology and Toxicology. It Presents toxicology data by intended route of administration in
the following order: 1. Oral 2. Intravenous 3. Intramuscular 4. Interperitoneal 5. Subcutaneous 6.
Inhalation 7. Topical 8. Other in vivo 9.In vitro NDA Section 5: Nonclinical Pharmacology and
Toxicology
For acute toxicity studies, present the animal study data in the following
order: 1. Mouse 2. Rat 3. Hamster 4. Other rodent(s) 5. Rabbit 6. Dog 7. Monkey 8. Other
nonrodent mammal(s) 9. Nonmammals NDA Section 5: Nonclinical Pharmacology and
Toxicology. It Presents the ADME data in the following order: 1. Absorption 2. Distribution
(protein binding, tissue distribution, accumulation) 3. Metabolism (enzyme induction or
inhibition) 4. Excretion (serum half-life, Key etc) NDA Section 5: Nonclinical Pharmacology
and Toxicology
NDA Section 6: Human Pharmacokinetics and Bioavailability: This technical section includes data from Phase I safety and tolerance
studies in healthy volunteers and ADME studies. It should include a table of PK parameters,
giving the values for the major parameters (mean and % cv) such as • Peak concentration (Cmax)
• Area under the curve (AUC) • Time to reach peak concentration (tmax) • Elimination constant
(Ke) • Distribution volume (Vd) • Plasma and renal clearance • Urinary excretion
It should include a list of all formulations used in clinical trials and in in
vivo bioavailability and PK studies. The analytical methods used must be summarized in each in
vivo biopharmaceutical study. Include detailed information, such as Sensitivity Linearity
Specificity and Reproducibility of the analytical test methods used in each study
It Provides dissolution data on each strength and dosage form for which
an approval is sought. Include a comparative dissolution study with the lot in the in vivo
biopharmaceutical study. Include summary of the product’s Dissolution performance Dissolution
method and Dissolution specifications, this technical section must include individual study
reports from five types of biopharmaceutical studies as described below: Pilot or background
studies Bioavailability/bioequivalence Pharmacokinetic studies other in vivo studies In vitro
studies
Pilot or background studies:
Pilot or background studies Pilot or background studies are carried
out in a small number of subjects to provide preliminary assessment of ADME information. It
acts as a guide to the design of early clinical trials and definitive kinetic studies.
Bioavailability/bioequivalence:
Bioavailability/bioequivalence Bioavailability studies define the
rate and extent of absorption relative to a reference dosage form, such as IV, solution, or
suspension. Bioequivalence studies compare pharmaceutical alternatives to establish equivalent
extents and, where necessary, equivalent rates of absorption. Dosage strength equivalence studies
show that equivalent doses of different dosage forms deliver the same amount of drug. For
example, three doses of 100 milligrams (mg) is equivalent to a single 300 mg tablet.
Pharmacokinetic studies:
Pharmacokinetic studies Designed to define the drug’s time course
and, where appropriate, major metabolite concentrations in the blood and other body
compartments. With these studies, it is critical to demonstrate the rate of drug absorption and
delivery to systemic circulation and the rate of elimination of the drug through metabolic or
excretory processes. Dose dependent changes in kinetic parameters are very important.
Pharmacokinetic studies Other information from PK studies may
include the influence of demographic characteristics such as age, gender, or race certain disease
states (e.g., cirrhosis) external factors such as meals or other drugs. Include information on
studies that show drug binding to biological constituents such as Plasma protein or red blood
cells Studies performed in special patient populations (e.g., Steroid-dependent patients), and
Studies performed under conditions of therapeutic use.
In vivo studies: In vivo studies include any bioavailability studies that employ
pharmacological or clinical measurements or endpoints in humans or animals. In addition,
chemical analysis of body fluids may be used when appropriate.
In vitro studies: In vitro studies In vitro studies should include studies designed to
define the release rate of a drug substance from the dosage form. Such studies are conducted in
order to characterize a dosage form and to assure consistent batch-to-batch behavior. Other in
vitro studies may be conducted for further characterization of the drug moiety (e.g., protein
binding).
NDA Section 7: Microbiology: Microbiology required for anti infective drug products.
Antimicrobial drugs differ from other classes of drugs in that they are designed to affect
microbial physiology rather than patient physiology. In vitro and in vivo studies are critical in
establishing the new drug’s effectiveness, especially if the microorganism has the potential to
develop, or has developed, resistance to other antimicrobial drugs. This section requires the
following technical information and data: 1. A complete description of the biochemical basis of
the drug’s action on microbial physiology. 2. The drug’s antimicrobial spectrum. Include results
of in vitro studies demonstrating the concentrations of the drug that are required for effective use.
3. Describe any known mechanisms of resistance to the drug and provide information or data of
any known epidemiologic studies demonstrating prevalence to resistance factors. 4. Clinical
microbiology laboratory methods, such as in vitro sensitivity discs, necessary to evaluate
effective use of the drug.
NDA Section 8: Clinical Data:
This technical section of the NDA comprises ten elements. The
document’s largest and most complex section. List of investigators and list of INDs and NDAs
Background/overview of clinical investigations Clinical pharmacology section Controlled
clinical trials Uncontrolled clinical trials other studies and information section Integrated
summary of effectiveness data Integrated summary of safety information Drug abuse and over
dosage information Integrated summary of benefits and risks of the drug.
List of investigators and list of INDs and NDAs:
List of investigators and list of INDs and NDAs the list of
investigators should include all investigators who have used any dosage form. Alphabetize the
list and note each investigator’s address, the type of study, the study identifier, and its location in
the NDA. Provide a list of all known INDs under which the drug, in any dosage form, has been
studied.
Background/overview of clinical investigations:
Background/overview of clinical investigations Describe the general
approach and rationale used in developing the clinical data. Explain how information about the
drug derived from clinical pharmacology studies led to critical features of the clinical studies.
Support the basis for the design features of the clinical trials, such as number of patients,
duration, selection criteria, and controls.
Clinical pharmacology:
Clinical pharmacology should include ADME studies,
pharmacodynamic dose range, and dose response studies, and any other studies of the drug’s
action. The format and order of presentation is as follows: 1. Table of all studies grouped by
study type. Provide the investigators, study numbers, start date, and location of the report in the
NDA. 2. For each group of studies, a brief synopsis of each study 3. An overall summary of the
clinical pharmacology data
Controlled clinical trials:
Controlled clinical trials provide the following material in the order
presented below: 1. A table of all studies 2. Full clinical trial reports of all controlled studies in
the following order: Completed studies ongoing studies with interim results Incomplete or
discontinued studies 3. Full reports of dose-comparison concurrent control studies, followed by
those for “no- treatment” concurrent control, active control studies, and historical control studies
Uncontrolled clinical trials:
Uncontrolled clinical trials they may be used to provide support for
controlled studies and to provide critical safety information. This section should include a table
of all studies. Group full reports of studies according to completeness and availability of Case
Report Forms (CRFs).
Other studies and information:
Other studies and information include a description and analysis of
any additional information that the applicant has obtained from any source, foreign or domestic,
that is relevant to evaluating the product’s safety and effectiveness. It should include information
on commercial marketing experience and foreign regulatory actions, including: List of countries
in which the drug has been approved Details of any rejected registrations Copies of approved
labeling (package inserts) from major regions such as Europe, Canada, Australia, New Zealand,
and Japan Any other reports from the literature not provided elsewhere in the NDA
Integrated summary of effectiveness:
Integrated summary of effectiveness Demonstrate substantial
evidence of effectiveness for each claimed indication. It should also include a summary of
evidence supporting the dosage and administration section of the labeling, including the dosage
and dose interval recommended.
Integrated summary of safety information:
Integrated summary of safety information incorporate safety data
from all sources, including pertinent animal data, Clinical studies, and foreign marketing
experience. Describe the demographics and other characteristics of the entire drug exposed
population and also of logical groups of studies.
NDA Section 9: Safety Update Reports:
A pending application must be updated when new safety data
becomes available that could affect any of the following: Statements in draft labeling
Contraindications Warnings Precautions Adverse events. Safety update reports are not to be used
to submit any new final reports that may impact FDA review time unless the FDA agrees at the
pre-NDA meeting that it will accept the reports in this manner. Safety updates are submitted 4
months (120 days) after the initial application, following the receipt of an approval letter and at
any other time that the FDA requests such an update.
NDA Section 10: Statistics:
This technical section includes descriptions and documentation of
the statistical analyses performed to evaluation the controlled clinical trials and other safety
information. It must include copies of: All controlled clinical trial reports integrated efficacy and
safety summaries integrated summary of risks and benefits.
NDA Section 11: Case Report Form Tabulations:
This section must include complete tabulations for each patient
from every adequately or well-controlled Phase II and Phase III efficacy study, and from every
Phase I clinical pharmacology study. It also must include tabulations of safety data from all
clinical studies.
NDA Section 12: Case Report Forms (CRFs):
It is necessary to include the complete CRF for each patient who
died during a clinical study and for any patients who were dropped from the study the report
must be submitted regardless of whether the AE is considered to be related to the study drug,
even if the patient was receiving a placebo or comparative drug. Additional CRFs must be
provided at the request of the FDA.
The NDA in CTD Format:
The NDA in CTD Format ICH has developed a Common
Technical Document to streamline regulatory submissions in Europe, the U.S. and Japan. CTD is
an information format that contains clinical, nonclinical, and manufacturing technical data. The
CTD format features well-defined modules, with a highly specific structure and numbering of
sections within the modules. It makes a clear distinction between subjective information sections
and objective information sections.
FLOWCHART:
Abbreviated New Drug Application (ANDA):
An Abbreviated New Drug Application (ANDA) contains
data which when submitted to FDA's Center for Drug Evaluation and Research, Office of
Generic Drugs, provides for the review and ultimate approval of a generic drug product. Once
approved, an applicant may manufacture and market the generic drug product to provide a safe,
effective, low cost alternative to the American public.
A generic drug product is one that is comparable to an
innovator drug product in dosage form, strength, route of administration, quality, performance
characteristics and intended use. All approved products, both innovator and generic, are listed in
FDA's Approved Drug Products with Therapeutic Equivalence Evaluation (Orange Book).
Generic drug applications are termed "abbreviated" because
they are generally not required to include preclinical (animal) and clinical (human) data to
establish safety and effectiveness. Instead, generic applicants must scientifically demonstrate
that their product is bioequivalent (i.e., performs in the same manner as the innovator drug). One
way scientists demonstrate bioequivalence is to measure the time it takes the generic drug to
reach the bloodstream in 24 to 36 healthy, volunteers. This gives them the rate of absorption, or
bioavailability, of the generic drug, which they can then compare to that of the innovator drug.
The generic version must deliver the same amount of active ingredients into a patient's
bloodstream in the same amount of time as the innovator drug.
Using bioequivalence as the basis for approving generic copies
of drug products was established by the "Drug Price Competition and Patent Term Restoration
Act of 1984," also known as the Waxman-Hatch Act. This Act expedites the availability of less
costly generic drugs by permitting FDA to approve applications to market generic versions of
brand-name drugs without conducting costly and duplicative clinical trials. At the same time, the
brand-name companies can apply for up to five additional years longer patent protection for the
new medicines they developed to make up for time lost while their products were going through
FDA's approval process. Brand-name drugs are subject to the same bioequivalence tests as
generics upon reformulation. For more information on generic drug bioequivalence
requirements, please see the chapter entitled "FDA Ensures Equivalence of Generic Drugs" in
"From Test Tube to Patient: Improving Health Through Human Drugs."
The Office of Generic Drugs provides additional information to
generic drug developers, focusing on how CDER determines the safety and bioequivalence of
generic drug products prior to approval for marketing. Generic drug application reviewers focus
on bioequivalence data, chemistry and microbiology data, requests for plant inspection, and drug
labeling information.
FLOWCHART:
DRUGS APPROVED BY FDA IN THE YEAR 2010
Cardiology/Vascular Diseases
Pradaxa (dabigatran etexilate mesylate); Boehringer Ingeleheim; For the risk reduction of stroke and embolism due to atrial fibrillation, Approved October 2010
Tekamlo (aliskiren + amlodipine); Novartis; For the treatment of hypertension, Approved August 2010
Tribenzor (olmesartan medoxomil + amlodipine + hydrochlorothiazide); Daiichi Sankyo; For the treatment of hypertension, Approved July 2010
Dermatology/Plastic Surgery
Veltin (clindamycin phosphate and tretinoin); Stiefel; For the treatment of acne vulgaris, Approved July 2010
Zyclara (imiquimod); Graceway; For the treatment of actinic keratoses of the face and scalp, Approved March 2010
Endocrinology
Prolia (denosumab); Amgen; For the treatment of postmenopausal women with osteoporosis at high risk for fracture, Approved June 2010
Victoza (liraglutide); Novo Nordisk; For the treatment of type 2 diabetes mellitus, Approved January 2010
Gastroenterology
Herceptin (trastuzumab); Genentech; For the treatment of gastric cancer, Approved October 2010
Pancreaze (pancrelipase); Johnson & Johnson; For the treatment of exocrine pancreatic insufficiency, Approved April of 2010
Vimovo (naproxen + esomeprazole); AstraZeneca; For the treatment of arthritis in patients at risk for NSAID-associated ulcers, Approved April 2010
Zuplenz (ondansetron oral soluble film); Strativa Pharmaceuticals; For the prevention of post-operative, chemotherapy and radiotherapy induced nausea and vomiting, Approved July 2010
Hematology
Vpriv (velaglucerase alfa for injection); Shire; For the treatment of type 1 Gaucher disease, Approved March 2010
Immunology/Infectious Diseases
Cayston (aztreonam for inhalation solution); Gilead Sciences; For the treatment of cystic fibrosis patients with Pseudomonas aeruginosa, Approved February 2010
Menveo (meningitis vaccine); Novartis; For the active immunization to prevent invasive meningococcal disease, Approved February 2010
Oravig (miconazole); Strativa Pharmaceuticals; oropharyngeal candidiasis, Approved April 2010
Prevnar 13 (Pneumococcal 13-valent Conjugate Vaccine); Wyeth; For the active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae, Approved February 2010
Zortress (everolimus); Novartis; For the prevention of organ rejection following kidney transplant, Approved May 2010
Zymaxid (gatifloxacin ophthalmic solution); Allergan; For the treatment of bacterial conjunctivitis, Approved May 2010
Musculoskeletal
Actemra (tocilizumab); Genentech; For the treatment of rheumatoid arthritis, Approved January 2010
Ampyra (dalfampridine); Acorda; For the improvement of walking in patients with multiple sclerosis, Approved January 2010
Botox (onabotulinumtoxinA); Allergan; For the treatment of upper limb spasticity, Approved March 2010
Gilenya (fingolimod); Novartis; For the treatment of relapsing multiple sclerosis, Approved September 2010
Krystexxa (pegloticase); Savient Pharma; For the treatment of chronic gout (hyperuricemia), Approved September 2010
Prolia (denosumab); Amgen; For the treatment of postmenopausal women with osteoporosis at high risk for fracture, Approved June 2010
Vimovo (naproxen + esomeprazole); AstraZeneca; For the treatment of arthritis in patients at risk for NSAID-associated ulcers, Approved April 2010
Xeomin (incobotulinumtoxinA); Merz Pharmaceutical; For the treatment of cervical dystonia and blepharospasm, Approved July 2010
Xiaflex (collagenase clostridium histolyticum); Auxilium Pharmaceuticals; For the treatment of Dupuytren’s contracture, Approved February 2010
Nephrology/Urology
Carbaglu (carglumic acid); Recordati; For the treatment of hyperammonemia, Approved March 2010
Jalyn (dutasteride + tamsulosin); GlaxoSmithKline; For the treatment of benign prostatic hyperplasia, Approved June 2010
Jevtana (cabazitaxel); sanofi aventis; For the treatment of prostate cancer, Approved June 2010
Provenge (sipuleucel-T); Dendreon; For the treatment of hormone refractory prostate cancer, Approved May 2010
Xifaxan (rifaximin); Salix; For the treatment of hepatic encephalopathy, Approved March 2010
Zortress (everolimus); Novartis; For the prevention of organ rejection following kidney transplant, Approved May 2010
Neurology
Ampyra (dalfampridine); Acorda; For the improvement of walking in patients with multiple sclerosis, Approved January 2010
Botox (onabotulinumtoxinA); Allergan; For the treatment of upper limb spasticity, Approved March 2010
Botox (onabotulinumtoxinA); Allergan; For the treatment of chronic migraine, Approved October 2010
Carbaglu (carglumic acid); Recordati; For the treatment of hyperammonemia, Approved March 2010
Cuvposa (glycopyrrolate); Shionogi; For the treatment of chronic severe drooling in pediatrics with neurologic conditions, Approved July 2010
Exalgo (hydromorphone hydrochloride) extended release; Alza; For the management of moderate to severe pain, Approved March 2010
Kapvay (clonidine hydrochloride); Shionogi Pharma; For the treatment of attention deficit hyperactivity disorder, Approved October 2010
Silenor (doxepin); Somaxon Pharma; For the treatment of insomnia, Approved March 2010
Sprix (ketorolac tromethamine); Roxro Pharma; For the treatment of moderate to severe pain, Approved May 2010
Vivitrol (naltrexone for extended-release injectable suspension); Alkermes; For the prevention of relapse to opioid dependence, Approved October 2010
Vpriv (velaglucerase alfa for injection); Shire; For the treatment of type 1 Gaucher disease, Approved March 2010
Xifaxan (rifaximin); Salix; For the treatment of hepatic encephalopathy, Approved March 2010
Obstetrics/Gynecology
ella (ulipristal acetate); HRA Pharma; For the emergency prevention of contraception, Approved August 2010
Natazia (estradiol valerate + dienogest); Bayer; For the prevention of contraception, Approved May 2010
Prolia (denosumab); Amgen; For the treatment of postmenopausal women with osteoporosis at high risk for fracture, Approved June 2010
Oncology
Herceptin (trastuzumab); Genentech; For the treatment of gastric cancer, Approved October 2010
Jevtana (cabazitaxel); sanofi aventis; For the treatment of prostate cancer, Approved June 2010
Provenge (sipuleucel-T); Dendreon; For the treatment of hormone refractory prostate cancer, Approved May 2010
Zuplenz (ondansetron oral soluble film); Strativa Pharmaceuticals; For the prevention of post-operative, chemotherapy and radiotherapy induced nausea and vomiting, Approved July 2010
Ophthalmology
Zymaxid (gatifloxacin ophthalmic solution); Allergan; For the treatment of bacterial conjunctivitis, Approved May 2010
Otolaryngology
Oravig (miconazole); Strativa Pharmaceuticals; oropharyngeal candidiasis, Approved April 2010
Pediatrics/Neonatology
Cuvposa (glycopyrrolate); Shionogi; For the treatment of chronic severe drooling in pediatrics with neurologic conditions, Approved July 2010
Dulera (mometasone furoate + formoterol fumarate dihydrate); Merck; For the treatment of asthma, Approved June 2010
Kapvay (clonidine hydrochloride); Shionogi Pharma; For the treatment of attention deficit hyperactivity disorder, Approved October 2010
Veltin (clindamycin phosphate and tretinoin); Stiefel; For the treatment of acne vulgaris, Approved July 2010
Pharmacology/Toxicology
Zuplenz (ondansetron oral soluble film); Strativa Pharmaceuticals; For the prevention of post-operative, chemotherapy and radiotherapy induced nausea and vomiting, Approved July 2010
Psychiatry/Psychology
Oleptro (trazodone hydrochloride); Labopharm; For the treatment of major depressive disorder, Approved February 2010
Vivitrol (naltrexone for extended-release injectable suspension); Alkermes; For the prevention of relapse to opioid dependence, Approved October 2010
Pulmonary/Respiratory Diseases
Cayston (aztreonam for inhalation solution); Gilead Sciences; For the treatment of cystic fibrosis patients with Pseudomonas aeruginosa, Approved February 2010
Dulera (mometasone furoate + formoterol fumarate dihydrate); Merck; For the treatment of asthma, Approved June 2010
Rheumatology
Actemra (tocilizumab); Genentech; For the treatment of rheumatoid arthritis, Approved January 2010
Krystexxa (pegloticase); Savient Pharma; For the treatment of chronic gout (hyperuricemia), Approved September 2010
Vimovo (naproxen + esomeprazole); AstraZeneca; For the treatment of arthritis in patients at risk for NSAID-associated ulcers, Approved April 2010
Trauma/Emergency Medicine
Zuplenz (ondansetron oral soluble film); Strativa Pharmaceuticals; For the prevention of post-operative, chemotherapy and radiotherapy induced nausea and vomiting, Approved July 2010
Conclusion:
Advances in the field of Genomics and Bioinformatics will help in the
identification of potential drug targets especially related to disease targets in the future. New
drugs for the genetic disorders such as Huntington’s disease, Alzheimer’s disease, cancer and
several polygenic diseases will become available. It is estimated that there are about 100 diseases
for which new drugs are required in the near future, which may provide about 10,000 different
new target sites for new drug discovery. Therefore, future is brimming with opportunity and
challenging in identifying the critical targets ad designing of safe and effective drugs that interact
with these targets.
REFERENCE:
• Ansel’s Pharmaceutical Dosage Forms & Drug Delivery Systems.
• Industrial Pharmacy By Lachhman Liebermann.
• www.innovation .org .com
• www.fda.gov.in
• www.sciencemag.org
• www. drug s.com/ new - drug - application s
• www.authorstream.com
• www.novartis.com/research/drug-discovery