Clinical Research.pptx

Principles Of Drug Discovery &
Development
MANSI NARENDRASINH CHAUHAN
M.Pharm

Product Development & Technology Transfer
Topic: Principles Of Drug Discovery & Development
Guided by
Dr. Sachin Narkhede &
Mrs. Neha Vadgama
Presented By
M.Pharm
Pharmaceutical Quality Assurance
Smt. BNB Swaminarayan Pharmacy College Salvav-Vapi

History
• Prior to the 20th century, the discovery of drug substances for the
treatment of human diseases was primarily a matter of “hit or miss”
use in humans, based on folklore and anecdotal reports. Many, if not
most, of our earliest therapeutic remedies were derived from plants
or plant extracts that had been administered to sick humans.
• Pioneers in the field of medicinal chemistry such as Paul Ehrlich,
were instrumental in initiating the transition from the study of plants
or their extracts with purported therapeutic activities to the deliberate
synthesis, in the laboratory, of a specific drug substance.
• Certainly, the discovery of the sulfa drugs in the 1930s added great
momentum to this concept, since they provided one of the earliest
examples of a class of pure chemical compounds that could be
unequivocally shown to reproducibly bring certain infectious
diseases under control when administered to patients by mouth.
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• During World War II, the development of penicillin stimulated an
enormous and highly motivated industry aimed at the random
testing of a variety of microbes, This activity was set into motion
by the discovery of Alexander Fleming and others in England in
1929 that a Penicillium mold produced tiny amounts of a substance
that was able to kill various bacteria.
• In addition to the scientific interest in these findings, a major need
existed during World War II for new medications to treat members
of the armed forces.
• Indeed, these efforts resulted in accelerated rates of discovery and
the enormous medical and commercial potential of the antibiotics,
which were evident as early as 1950, assured growth and longevity
to this important new industry. Major pharmaceutical companies
such as Abbott Laboratories, Eli Lilly, E. R. Squibb & Sons, Pfizer
Pharmaceuticals, and The Upjohn Company in the United States.

• In the 1960s and 1970s, chemists again came heavily into the
infectious diseases’ arena and began to modify the chemical
structures produced by the microorganisms, giving rise to the so-
called semi-synthetic antibiotics.
• The truly impressive rate of discovery of the ‘semi-synthetic’
antibiotics was made possible by the finding the penicillin and
cephalosporin classes of antibiotics.
• In the later quarter of the 20th century, an exciting new technology
emerged into the pharmaceutical scene, namely, biotechnology.
Using highly sophisticated, biochemical genetic approaches,
significant amounts of proteins, which, prior to the availability of
genetic engineering.
• In the mid- to late 20th century, primarily as a result of the major
screening and chemical synthetic efforts in the pharmaceutical
industry in industrialized countries worldwide, but also as a result
of the biotechnology revolution, increased the need for
sophistication and efficacy.

Introduction
 The creation of a new drug can be broadly divided into three main
phases:
Drug discovery – from therapeutic concept to molecule
Drug development – from molecule to registered product
Commercialization – from product to therapeutic application to sales.
• The discovery team, having delivered the first candidate drug, will
carry on looking for others, to serve as back-ups in case the lead
compound should fail in development, or as follow-up compounds
intended to have advantages over the lead compound.
• The three components of the overall process are not independent and
consecutive stages, but have to be closely coordinated at all stages of
the project.
• At the outset of any new project, the criteria against which the plan
will be judged include not only its scientific strength and originality
but, importantly, development and marketing issues.

Drug Discovery
• Drug discovery can be described as the process of identifying
chemical entities that have the potential to become therapeutic
agents.
• A key goal of drug discovery campaigns is the recognition of new
molecular entities that may be of value in the treatment of diseases
that qualify as presenting unmet medical needs.
• The drug discovery phase of a typical project aimed at producing a
new synthetic drug, starts with the choice of a disease area and
defining the therapeutic need that is to be met.
• It proceeds to the identification of the biochemical, cellular or
pathophysiological mechanism that will be targeted, and, if
possible, the identification and validation of a molecular ‘drug
target’.
• Next comes the identification of a lead structure, followed by the
design, testing and fine tuning of the drug molecule to the point
where it is deemed suitable for development.

Drug Development
• Drug development comprises all the activities involved in
transforming a compound from drug candidate (the end-product of
the discovery phase) to a product approved for marketing by the
appropriate regulatory authorities. Efficiency in drug development
is critical for commercial success, for two main reasons:
• Development accounts for about two-thirds of the total R&D costs.
The cost per project is very much greater in the development phase,
and increases sharply as the project moves into the later phases of
clinical development. Keeping these costs under control is a major
concern for management. Failure of a compound late in
development represents a lot of money wasted.
• Speed in development is an important factor in determining sales
revenue, as time spent in development detracts from the period of
patent protection once the drug goes to market. As soon as the
patent expires, generic competition sharply reduces sales revenue.
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The Nature of drug development
 Drug discovery, is invariably an exploration of the unknown, and
successful projects may end up with compounds quite different from
what had originally been sought there is a large component of
‘unplannability’. In contrast, drug development has a very clear-cut
goal
• To produce the drug in a marketable form
• To gain regulatory permission to market it for use in the target
indication as quickly as possible.
 The work required to do this falls into three main parts,
respectively:
• Technical
• Investigative
• Managerial

Technical development:
• Solving technical problems relating to the synthesis and
formulation of the drug substance, aimed mainly at ensuring the
quality of the end-product.
• Main functions involved: chemical development, pharmaceutical
development.
Investigative studies:
• Establishing the safety and efficacy of the product, including
assessment of whether it is pharmacokinetically suitable for clinical
use in man.
• Main functions involved: safety pharmacology, toxicology,
pharmacokinetics, clinical development.

Managerial functions:
• Coordination – managing quality control, logistics,
communication and decision making in a large
multidisciplinary project to ensure high-quality data and
to avoid unnecessary delays:
• Main function involved: project management
• Documentation and liaison with regulatory authorities –
collating and presenting data of the type, quality and
format needed to secure regulatory approval
• Main function involved: regulatory affairs.

Components of drug development
• The components of drug development summarizes the
main activities involved in developing a typical
synthetic compound.
• It shows the main tasks that have to be completed
before the compound can be submitted for regulatory
approval, but needs to be translated into an operational
plan that will allow the project to proceed as quickly
and efficiently as possible.
• It is obvious that certain tasks have to be completed in a
particular order.

Clinical research process
M.Pharm

Introduction
• While preclinical research provides answers to basic questions
about a drug’s safety, it is not a substitute for studies of ways the
drug will interact with the human body.
• “Clinical research” refers to studies, or trials, that are done in
people. As the developers design the clinical study, they will
consider what they want to accomplish for each of the different
Clinical Research Phases and begin the Investigational New Drug
Process (IND), a process they must go through before clinical
research begins.
• The clinical development stream is the most complex part of the
drug development process. It also extensively consumes financial
and human resources.

Objectives
• The objectives of clinical development of a drug candidate are
to:
1) Study the pharmacological and pharmacokinetic features of
the drug in healthy volunteers and patients,
2) Determine the required dose range and dosing regimen of
the drug to validate its therapeutic efficacy and safety in
targeted population,
3) Study drug-drug and drug-food interactions,
4) Establish a positive benefit-to-risk ratio in patients,
5) Determine the drug's optimal conditions of use in clinical
practice, and
6) Explore new indications, formulations and combinations of
the drug.

Designing clinical trials
Researchers design clinical trials to answer specific research questions
related to a medical product. These trials follow a specific study plan,
called a protocol, that is developed by the researcher or manufacturer.
Before a clinical trial begins, researchers review prior information
about the drug to develop research questions and objectives. Then, they
decide:
• Who qualifies to participate (selection criteria)
• How many people will be part of the study
• How long the study will last
• Whether there will be a control group and other ways to limit research bias
• How the drug will be given to patients and at what dosage
• What assessments will be conducted, when, and what data will be collected
• How the data will be reviewed and analyzed

Clinical research phase studies
• After the preclinical research, the tests and treatments undergo a
series of clinical trials to evaluate if the tests or treatments are safe
and effective for the human subjects. Clinical trials are conducted in
the following five phases:
• 1) Phase 0: The trials of this phase are the first clinical trials
conducted in human subjects. Their objective is to learn the
processes a drug undergoes within the body and the effect it
produces in the body. In these trials, 10 to 15 human subjects are
administered with a very small dose of the drug.
• 2) Phase I: The trials of this phase are conducted to determine that
dose of a new drug which will produce the least side effects. In
these trials, the drug is tested in 15 to 30 patients. The physicians
administer the drug to a few patients in very low doses, and in other
patients the drug is given in high doses till the time either severe
side effects are produced or the desired effect is observed. Phase I
trials are conducted to test whether or not the drug under study is
safe. If it is found to be sufficiently safe, it is processed further for
phase II clinical trial.

3) Phase II: The trials of this phase evaluate the safety and
effectiveness of the of cancer. These rising new drug The drug is
tested in patients having a specific type of cancer trials are conducted
in a large number of patients using new combinations. Patients are
monitored to check the drug effect, and it found to be effective, it is
processed further for phase III clinical trial.
4) Phase III: The trials of this phase compare a new drug to the
standard care drug being used. These trials are conducted in around
100 or patients to evaluate the side effects of each drug and determine
the do showing better efficacy. These trials are generally randomized,
i.e. patients are randomly put into a treatment group, called trial arms,
using a computer program. Randomization ensures that the people in
all the trio arms are identical. This also allows the scientists to identify
that the clinical trial results are the outcomes of treatment and not the
differences between the groups.

• Phase III trials can involve more than two treatment groups. The
control group gets the standard-of-care treatment, and the other
groups get a new treatment. Neither the patients nor their physician
can choose the group. The patients will even not know their group
until the trial ends. If the new drug produces severe side effects or
if one group shows much better results, the phase III trial is stopped
early. Phase III clinical trials are conducted before the FDA
approves the use of a new drug for the public.
5) Phase IV: The trials of this phase are conducted to test the FDA-
approved new drugs in several hundreds or thousands of patients.
This allows for better research on short-lived and long-lasting side
effects and safety. In some cases, some rare side effects are only
found in large groups of people. The physicians can also learn about
the drug efficacy alone and when used with other treatments.

The Investigational New Drug Process
• Drug developers, or sponsors, must submit an Investigational New
Drug (IND) application to FDA before beginning clinical
research.
In the IND application, developers must include:
1. Animal study data and toxicity (side effects that cause great
harm) data
2. Manufacturing information
3. Clinical protocols (study plans) for studies to be conducted
4. Data from any prior human research
5. Information about the investigator

Asking for FDA Assistance
• Drug developers are free to ask for help from FDA at any point in
the drug development process, including:
1. During the Pre-IND application, to review FDA guidance
documents and get answers to questions that may help enhance
their research
2. After Phase 2, to obtain guidance on the design of large Phase 3
studies
3. Any time during the process, to obtain an assessment of the IND
application
• Even though FDA offers extensive technical assistance, drug
developers are not required to take FDA’s suggestions. As long as
clinical trials are thoughtfully designed, reflect what developers
know about a product, safeguard participants, and otherwise meet
Federal standards, FDA allows wide latitude in clinical trial design.

FDA IND Review Team
The review team consists of a group of specialists in different scientific fields.
Each member has different responsibilities.
Project Manager: Coordinates the team’s activities throughout the review
process, and is the primary contact for the sponsor.
Medical Officer: Reviews all clinical study information and data before,
during, and after the trial is complete.
Statistician: Interprets clinical trial designs and data, and works closely with
the medical officer to evaluate protocols and safety and efficacy data.
Pharmacologist: Reviews preclinical studies.
Pharmakineticist: Focuses on the drug’s absorption, distribution,
metabolism, and excretion processes. Interprets blood-level data at different
time intervals from clinical trials, as a way to assess drug dosages and
administration schedules.
Chemist: Evaluates a drug’s chemical compounds. Analyzes how a drug was
made and its stability, quality control, continuity, the presence of impurities,
etc. 3/28/2022 MANSICHAUHAN-SMTBNBSPCsalvav-vapi 26

Approval
• The FDA review team has 30 days to review the original IND
submission. The process protects volunteers who participate in
clinical trials from unreasonable and significant risk in clinical
trials. FDA responds to IND applications in one of two ways:
1. The FDA gives Approval to begin clinical trials.
2. The FDA puts a Clinical hold to delay or stop the investigation.
FDA can place a clinical hold for specific reasons, including:
I. Participants are exposed to unreasonable or significant risk.
II. Investigators are not qualified.
III. Materials for the volunteer participants are misleading.
IV. The IND application does not include enough information about
the trial’s risks.

Clinical research protocol
1. General information
2. Background information
3. Study objectives and purpose
4. study design
5. Selection and withdrawal of participant
6. Treatment of participants
7. Assessment of efficacy
8. Assessment of safety
9. Statistics
10. Direct access to source data or documents
11. Quality control and quality assurance
12. Ethics
13. Data management
14. Financing and insurance
15. Publication policy
16. Supplements

References
• Leon Lachman, Herbert A. Liberman, Joseph L. Kaing. (1987). Third edition. “The
theory and practice of industrial pharmacy”. Varghese publishing house. Page no.
966-975.
• Ilango K. D., Shukla V. K., Lakade S. H. (2020). “Industrial pharmacy II”. Thakur
publication PVT. LTD. Page no. 127-135.
• Mann, R.D., Modern Drug Use: “An Enquiry on Historical Principles”, MTP Press,
Lancaster, England, 1984, pp. 1–769.
• G. Smith Charles, James T. O'Donnell. (2006). Second edition. “The Process of New
Drug Discovery and Development”. Informa health care USA Inc. page no. 1-4.
• Raymond G Hill, Humphrey P. Rang. (2013). Second edition. “Drug Discovery and
Development”. Elsevier Ltd. Page no. 123-531.
• www.fda.gov.htm
• www.sciencedirect.com.htm

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