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Overview of the steps involved in the discovery and development of a new
drug ( with schematic representation)
The following events takes place between the birth of a new drug substances & its marketing--A newly discovered drug substance is tested in a pharmacological screen.
In pharmacological screening the drug may be found sufficiently interesting to warrant
further study.
If so, the sufficient quantity of the drug substances is synthesized/ isolated to--a. perform initial toxicity studies
b. do initial analytical works &
c. do initial preformulation.
Once past initial toxicity studies, phase I clinical testing (clinical pharmacology) begins
& there is need of actual formulation.(although dose level may not yet be determined)
Phase ii & iii clinical testing then begins & during this phase (preferably phase ii) an
order of magnitude of formula is finalized.
After completion of the above, an NDA is submitted.
After approval of the NDA, production can start (product launch).
New Chemical Entity
Preclinical Studies
Investigational New
Drug Application (IND)
Clinical Trials
Preclinical Studies (continued)
-term animal toxicity
New Drug Application (NDA)
FIGURE: The new drug development process from discovery through preclinical and clinical
studies, FDA review of the new drug application, and post marketing activities.
Topic: 2
Schematic representation of the time course for the discovery and
development of a new drug
New drug
Preclinical studies
Clinical trials
i)Initial physico-chemical Phase I
Phase II
Phase III
short term
ii)Manufacture and
iii)Isolation from
long term
iii)Package & label
Average 6.5 years
Average 7 years
Average 1.5
IND submitted
FDA 30- days safety review
NDA submitted
Figure: New drug development process (FDA approach
Topic: 3
Sources of new drugs with examples
1)Natural Sources
Micro organism
Venoms and toxins
Marine sources
i)Phase iv
clinical studies
ii)Adverse reaction
iii)Product defect
NDA approved
2)Synthetic Sources
3)Semi Synthetic Sources
4)Recombined DNA technology and monoclonal antibodies
5)Gene Therapy
(1) Natuaral Sources
Plant materials: these include leaves, flowers, fruits, seeds, roots, bark, stem
a) The chemical reserpine isolated from Rauwolfia serpentina is a tranquilizer and a
hypotensive agent
b) Plant extracts (vinblastin and vincristine) from Vinca rosea exhibit antitumor
Animals have served humans in their search for drugs in a number of ways.
a) Hormonal substances such as thyroid extract insulin and pituitary hormone
obtained from the endocrine glands of cattle, sheep and swine
b) The urine of pregnant mares is a rich source of estrogens
c) Poliomyelitis vaccine is prepared in cultures of renal monkey tissue
(iii) Microbial Sources: Bacterial, Fungi, Moulds important source of many live serving drug.
Penicilium notatum
Penicillin griseofullivum
(iv) Mineral Sources:
Iron in iron deficiency anemia mercurial salts in syphilis Gold salts in rheumatoid
(v) Venom and Toxins
Teprotide from Brazilian viper has antihypertensive effect
(vi) Marine Sources:
Bryostatins, dolastatins are antitumor agents.
(2) Synthetic Sources:
When the nucleus of the drug from natural source as well as its chemical structure is
altered, we call it synthetic
Example: a series of quinolone- 3- carboxamide intermediates were found to have
antiviral activity.
(3) Semi Synthetic Sources
When the nucleus of drug obtained from natural source is retained but the chemical
structure is altered we call it synthetic.
For example: The various species of Dioscorea, popularly known as maxican yams, are
rich in the chemical steroid from which cortisone and estrogens are semi synthetically
(4) Recombinant DNA technology and Monoclonal antibodies:
Drug products as human insulin, human growth hormone, hepatitis B vaccine, epoetinalpha and interferon are being produced in Recombinant DNA technology Monoclonal
antibodies are used in home pregnancy testing produces.
(5) Gene Therapy:
A medical intervention based on modification of the genetic material of living cells
Application of gene therapy to treat
_ sickle cell anemia
_ malignant melanoma
Various Methods Of Drug Discovery With Example
Random or untargeted screening:
Random or untargeted screening involves the testing of large numbers of synthetic organic
compounds or substances of natural origin for biologic activity.
To detect and evaluate biologic activity, bioassays are used to differentiate the effect and potency
(strength of effect) of the test agent from those of controls of known action and effect.
High-throughput screening:
Newer methods, such as high-throughput screening, are capable of examining 15,000 chemical
compounds a week using 10 to 20 biologic assays (23). To be effective, this requires a sizable
and chemically diverse collection of compounds to examine, which many pharmaceutical and
chemical companies have in chemical libraries.
Molecular modification:
Molecular modification is a chemical alteration of a known and previously characterized organic
compound (frequently a lead compound; see next section) for the purpose of enhancing its
usefulness as a drug.
The molecular modifications may be slight or substantial, involving changes in functional
groups, ring structures, or configuration.
The molecular modifications that led to the discoveries of the first commercial beta-blocker,
propranolol, and the first commercial histamine H2-receptor blocking agent, cimetidine.
Mechanism-based drug design:
Mechanism-based drug design is molecular modification to design a drug that interferes
specifically with the known or suspected biochemical pathway or mechanism of a disease
process. The intention is the interaction of the drug with specific cell receptors, enzyme systems,
or the metabolic processes of pathogens or tumor cells, resulting in a blocking, disruption, or
reversal of the disease process.
An example of mechanism-based drug design is the compound enalaprilat, the active metabolite
of enalapril (Vasotec), which inhibits the angiotensin-converting enzyme (ACE) that catalyzes
the conversion of angiotensin I to the vasoconstrictor substance angiotensin II. Inhibition of the
enzyme results in decreased plasma angiotensin II, leading to decreased vasopressor effects and
lower blood pressure.
Topic: 9
International Conference On Harmonizition Of Technical Requirments For
Registration Of Pharmaceuticals For Human Use
The International Conference on Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH) is a tripartite organization formed in 1991 by the FDA,
the European Union and Japan and geographical representatives to discuss, identify, and address
relevant regulatory issues.
areas quality, safety, and
With ICH success,
-duplicative technical requirements for registering pharmaceuticals would be eliminated;
-new drug approvals would occur more rapidly;
-the quality, safety, and efficacy of imported products would be improved; and
-there would be an increase in information transfer between participating countries
Examples of specific ICH- developed guidelines:
-derived Pharmaceuticals
tissue distribution studies
response information to support drug regist
Investigational New Drug Application (IND)
An Investigational New Drug Application (IND) is a request for Food and Drug Administration
(FDA) authorization to administer an investigational drug to humans. Such authorization must be
secured prior to interstate shipment and administration of any new drug that is not the subject of
an approved new drug application.
An IND is required for a clinical study if it is intended to support a:
New indication.
Change in the approved route of administration or dosage level.
Change in the approved patient population (e.g. pediatric) or a population at greater or
increase of risk (Elderly, HIV positive, Immunocompromised).
Significant change in the promotion of an approved drug.
Purpose of IND:
FDA approval is needed to bring a new drug to market, and IND is a preliminary step in
that process. It is against federal law to transport an unapproved, unlabeled drug across
state lines.
Most clinical trials require participation from patients in various locations, and that presupposes sending the new drug to various states. An IND is exempt from this distribution
An IND can also be used for early permission to use a drug for treatment. Once a drug
enters the clinical research phase, it is deemed safe for people with reasonable certainty.
Although it is not legal to sell a drug at this point, some patients may not be able to wait
for final approval.
Content of The IND:
The content of an IND is prescribed in the Code of Federal Regulations and is submitted under a
cover sheet (Form FDA-1571). These are:
Name, address, and telephone number of the sponsor of the drug
Name and title of the person responsible for monitoring the conduct and progress of
the investigation
Names and titles of the persons responsible for the review and evaluation of the
information relevant to the safety of the drug
Name and address of any contract research organization involved in the study
Introductory statement and general investigational plan: the name of the drug and all
formulation of the dosage form and route of administration, and the broad objectives
and planned duration of the study
Description of the investigational plan: the rationale for the drug or research study,
the indication or indications to be studied, the approach to evaluating the drug, the
types of studies to be conducted, the estimated number of subjects to be given the
drug, and any serious risks anticipated based on animal studies or other human
experiences with the drug
Brief summary of previous human experience with the drug (domestic or foreign),
including the reasons if the drug has been withdrawn from any other investigation
and/or marketing
CMC information: a complete description of the drug substance, including its
physical, chemical, and biologic characteristics; its method of preparation and
analytical methods to ensure its identity, strength, quality, purity, and stability; a
quantitative list of the active and inactive components of the dosage form to be
administered; the methods, facilities, and controls employed in the manufacture,
processing, packaging, and labeling of the new drug to ensure appropriate qualitative
and quantitative standards; and product stability during the clinical investigation
acute, sub-acute, chronic, and reproductive and developmental toxicity studies
If the new drug is a combination of previously investigated components, a complete
preclinical and clinical summary of these components when administered singly and
any data or expectations relating to the effect when combined
Clinical protocol for each planned study
Commitment that an Institutional Review Board (IRB) has approved the clinical
study and will continue to review and monitor the investigation
Investigator brochure
Commitment not to begin clinical investigations until the IND is in effect, the
signature of the sponsor or authorized representative, and the date of the signed
IND Submission Process:
Step 1: Pre-IND teleconference with FDA
Highly recommended for new products
Step 2: Submission of complete IND package
All forms, all sections
Step 3: IND Review
FDA will notify Sponsor within 30 calendar days of receipt of the IND whether the study
may proceed or is placed on clinical hold
Studies may not begin until 30 day review is complete or FDA notifies Sponsor studies
may proceed
IND Review Process:
Figure: IND Review Process
The Clinical Protocol:
As a part of the IND application, a clinical protocol must be submitted to ensure the appropriate
design and conduct of the investigation.
Clinical protocols include:
Statement of the purpose and objectives of the study
Outline of the investigational plan and study design, including the kind of control group
and methods to minimize bias on the part of the subjects, investigators, and analysts
Estimate of the number of patients to be involved
Basis for subject selection, with inclusion and exclusion criteria
Description of the dosing plan, including dose levels, route of administration, and
duration of patient exposure
Description of the patient observations, measurements, and tests to be used
Clinical procedures, laboratory tests, and monitoring to be used in minimizing patient risk
Names, addresses, and credentials of the principal investigators and coinvestigators
Locations and descriptions of the clinical research facilities to be use
Approval of the authorized IRB
Treatment IND:
A treatment IND or a treatment protocol permits the use of an investigational drug in the
treatment of patients not enrolled in the clinical study but who have a serious or immediately
life- threatening disease for which there is no satisfactory alternative therapy. The objective is to
make promising new drugs available to desperately ill patients as early as possible in the drug
disease in which there is a reasonable likelihood that death will occur within a matter of months
or in which premature death is lik
. This includes such conditions as
advanced cases of AIDS, herpes simplex encephalitis, advanced metastatic refractory cancers,
bacterial endocarditis, Alzheimer disease, advanced multiple sclerosis, advanced Parkinson
disease, and others.
For products to be considered for a treatment IND, the drug must be under active investigation in
cacy demonstrated to
data, a drug may be approved for treatment use during Phase 2 or Phase 3 of the clinical trials. In
sponsor must submit a treatment protocol in addition to the
information normally included in an IND application. In making its decision, the FDA renders a
treatment IND, the law provides for the emergency use of an investigational drug in rare
IND For an Orphan Drug:
or condition that affects fewer than 200,000 people in the United States and for which there is no
reasonable expectation that costs of research and development for the indication can be
recovered by sales of the product in the United States. Examples of such illnesses are- chronic
lymphocytic leukemia,
elopment was established to identify and facilitate the
development of orphan products, including drugs, biologics, and medical devices. To foster the
necessary research and development, the FDA provides support grants to conduct clinical trials
on safety
grants are awarded for Phase 2 and Phase 3 clinical studies based on preliminary clinical
research. Regular and treatment IND protocols may be included in orphan drug clinical trials. An
incentive to orphan product development is a provision for a 7-year period of exclusive
marketing rights after regulatory approval of a product.
Clinical Investigation / Trial
A clinical trial is a carefully designed study which tests the benefits and risks of a specific
medical treatment or intervention, such as a new drug or a behavior change (e.g., diet). Once
researchers have completed a rigorous screening and preclinical testing process, the company
files an Investigational New Drug (IND) application with the U.S. Food and Drug
Administration (FDA). This application allows the investigational medicine to be tested in
human volunteers in clinical trials.
Purpose of Clinical Trial:
Assess safety and efficacy of:
Experimental treatments
New combinations of drugs
New approaches to surgery or radiation therapies
Better disease prevention approaches
Better diagnostic approaches
Phases of Clinical Trial:
ic questions.
The different phases of clinical trials are given below below:
Phase I:
These trials are used to test brand new drugs, devices or procedures to find out how safe they are,
including safest dose, and identify possible side effects. They usually involve 20 to 80 people.
Phase II:
These trials are used to further evaluate the effectiveness of a drug, device or procedure. The
researchers keep track of any medical benefits, as well as side effects. They usually involve 100
to 300 people. At the end of Phase II trials, the U.S. Food and Drug Administration (FDA) and
trial sponsors determine how Phase III trials will be conducted.
Phase III:
These trials compare a new treatment or procedure to current treatments to figure out which
works better. Safety and level of effectiveness continued to be monitored, as well as side effects.
They usually involve 1,000 to 8,000 people.
Phase IV:
Once a drug or procedure is approved by the FDA and made available to the public, researchers
continue to study its safety to figure out the best use of the new treatment. Information is
-term effectiveness in various populations, as well as adverse side
effects associated with long-term use.
Purposes of Different Phases:
Controlled Clinical Study:
Controlled clinical study is a research strategy that calls for two samples: an experimental sample
of patients receiving a pharmaceutical, and a second sample of control patients receiving a
placebo (placebo control) or an active drug (positive control), a standard or comparator drug
product. Both a placebo and an active drug may be used as controls in the same study. Neither
the patient nor the researcher knows which is receiving the pharmaceutical and which the
Blinded Study:
A study done in such a way that the patients or subjects do not know (is blinded as to) what
treatment they are receiving to ensure that the results are not affected by a placebo effect (the
power of suggestion).
Two types:
Single-blinded Study
Double-blinded Study
Single-blinded Study:
A type of clinical trial in which only the researcher doing the study knows whether a patient is
receiving the standard treatment or the new treatment being tested. This helps to prevent bias in
treatment studies.
Double-blinded study:
A medical study in which both the subjects participating and the researchers are uaware of when
the experimental medication or procedure has been given.
Open-labelled Study:
A type of study in which both the health providers and the patients are aware of the drug or
treatment being given.
Parallel Study Design:
A parallel design, also called a parallel group study, compares two or more treatments.
Participants are randomly assigned to either group, treatments are administered, and then the
key element of a parallel design.
Figure: Some Clinical Trial Parallel Study Design
Crossover Study Design:
A crossover design is a repeated measurements design such that each experimental unit (patient)
receives different treatments during the different time periods, i.e., the patients cross over from
one treatment to another during the course of the trial.
Figure: Some Clinical Trial Crossover Study Design
Crossover designs are useful in comparing different treatments within individuals since
following one treatment, a patient is crossed over to a different treatment. Between treatment
periods, subjects may be given no drugs as a washout period to allow return to baseline.
New Drug Application (NDA)
The NDA application is the vehicle through which drug sponsors formally propose that the FDA
approve a new pharmaceutical for sale and marketing in the U.S.
If the three phases of clinical testing during the IND(Investigational New Drug Application)
period demonstrate sufficient drug safety and therapeutic effectiveness, the sponsor may file an
NDA with the FDA. This filing may be preceded by a pre-NDA meeting between the sponsor
and the FDA to discuss the content and format of the NDA.
package insert) is appropriate.
adequate to preserve the drugs identity, strength, quality, and purity.
After all ,to gain permission to market the drug product in the United States.
General Content of the NDA:
nonproprietary, code, and proprietary names of the drug, the dosage form, its
strength, and route of administration .
as an OTC product .
intended labeling, CMCs, nonclinical and clinical pharmacology and toxicology, human
pharmacokinetics and bioavailability, statistical analysis, clinical trial data, benefit and risk
considerations, and proposed additional or planned post marketing studies.
chemical characteristics, methods of identification, assay, and controls, and the drug product,
including its composition, specifications, methods of manufacture and equipment used, inprocess controls, batch and master production records, container and closure systems, stability,
and expiration dating.
for nonclinical pharmacology and toxicology in relation to the
proposed therapeutic indication, including acute, subacute, and chronic toxicology,
carcinogenicity, reproductive toxicology, and animal studies of absorption, distribution,
metabolism, and excretion.
microbiology for antibiotic applications.
to the proposed indication, a copy of the study protocol, effectiveness and safety data including
any updates on safety information, comparison of human and animal pharmacology and
toxicology data, and support for the dosage and dose intervals and modifications for specific
subgroups such as pediatric, geriatric, and renally mpaired subjects.
oposed for marketing, reference standards, and
finished market package, as requested.
The applicant submits three copies of the NDA:
An archival copy, maintained by the FDA as the reference document;
A review copy, used by the FDA review division; and
A field copy, used by the FDA district office and field inspectors in an on-site preapproval
inspection .
FDA Review and Action Letters :
The completed NDA is carefully reviewed by the FDA. By regulation, the FDA must respond
within 180 days of receipt of an application. This 180-day period is called the review clock and
is often extended by agreement between the applicant and the FDA, as additional information,
studies, or clarifications are sought. The NDA is reviewed by the same FDA division that
recommendation of an outside advisory review committee composed of persons of recognized
the entire review of the application is completed.
The FDA can respond to a sponsor of an NDA with one of the following types of letters:
1. Approval, meaning the drug has met agency standards for safety and efficacy and the drug
can be marketed for sale in the United States.
2. Complete response, letting a company know that the review period for a drug is complete and
that the application is not yet ready for approval. The letter will describe specific deficiencies
and, when possible, will outline the recommended actions the applicant might take to get the
application ready for approval.
After an NDA is approved and the product marketed, the FDA requires periodic safety and other
reports, schedules plant inspections, and requires continued compliance with control and quality
standards and current good manufacturing practices.
Supplemental New Drug Application (SNDA):
A sponsor of an approved NDA may make changes in that application through the filing of an
Examples of changes that may be made without prior approval are minor editorial or other
changes in the labeling that add to or strengthen an approved label section, any analytical
changes made to comply with the USP
on full shelf-life data obtained from a protocol in the approved application, and a change in the
size (not the type of system) of the container for a solid dosage form.
Abbreviated New Drug Application (ANDA):
An ANDA is an application for a U.S. generic drug approval for an existing licensed medication
or approved drug.
An ANDA is one in which nonclinical laboratory studies and clinical investigations may be
for duplicates (generic copies) of drug products previously approved under a full NDA and for
which the FDA has determined that information on the exempted nonclinical and clinical studies
is already available at the agency.
Biologics License Application (BLA):
products, vaccines, and toxins. The applications for biologics approvals follow the regulatory
requirements as stated specifically for these products in the relevant parts of the CFR (4).
Animal Drug Applications:
The Federal Food, Drug, and Cosmetic Act, as amended, contains specific regulations pertaining
to the approval for the marketing and labeling of drugs intended for animal use .It allows
veterinarians to prescribe extra label uses of approved animal drugs and approved human drugs
for animals.