Drug development process

Drug Development Process
Clinical research
Unit 1
05/21/191 DR.GAURAV KUMAR (PHARMD, CPPM, CGCPh)

Step
 Step 1: Discovery and Development
 Step 2: Preclinical Research
 Step 3: Clinical Research
 Step 4: FDA Drug Review
 Step 5: FDA Post-Market Drug Safety Monitoring

05/21/19DR.GAURAV KUMAR (PHARMD, CPPM, CGCPh)5
Step 1: Discovery and Development
1. Drug discovery: is the process of identifying
compounds that have the potential to become useful
new therapies. The potential must be sufficient to
justify further research and development. Find a
promising molecule (a “lead compound”) that could
become a drug.
2. Pre-discovery: Understand the disease.
3. Target Identification: Choose a molecule to target
with a drug.
4. Target Validation: Test the target and confirm its
role in the disease.
1. Disease process: allow researchers to design a
product to stop or reverse the effects of the
disease.
2. Many tests of molecular compounds: to find
possible beneficial effects against any of a large
number of diseases.
3. Unanticipated effects: Existing treatments.
4. Target medical products: specific sites within
the body or to manipulate genetic material.
5. Medical treatment: At this stage in the process,
thousands of compounds may be potential
candidates for development.
6. After early testing: only a small number of
compounds look promising and call for further
study.

Discovery of biopharmaceuticals
1. Pharmaceutical discovery.
2. Specific diseases: Focusing on specific diseases and patient needs.
3. Biological targets: Scientists search for biological targets within the body that play a role in a given
disease.
4. Drug targets: can be part of the body (such as a protein, receptor, or gene).
 Researchers work to:
1. Validate these targets.
2. Discover the right molecule: (potential drug) to interact with the target chosen.
3. Test the new compound: in the lab and clinic for safety and efficacy.
4. Hands over to doctors and patients: after getting approval of new drug.

Drugs Discovery methods
1. Random Screening: The process of finding a new drug against a chosen target for a particular
disease.
2. Molecular Manipulation
3. Molecular Designing
4. Drug Metabolites
Pharmacogenetics
Pharmacogenetics: to studying the pattern of expression of gene products involved in a drug response.
Lead Optimization
A.To optimize potential drug molecules.
B.By changing the structure of a compound, scientists can give it different properties.
C.Lead compounds that survive the initial screening are then “optimized,” or altered to make them
more effective and safer.

Development
Once researchers identify a promising compound for development, they conduct experiments to gather
information on:
1. How it is absorbed, distributed, metabolized, and excreted.
2. Its potential benefits and mechanisms of action.
3. The best dosage.
4. Route of administration
5. Toxicity: Side effects or adverse events.
6. How it affects different groups of people (such as by gender, race, or ethnicity) differently.
7. Drug drug interaction.
8. Drug food interaction.
9. Its effectiveness as compared with similar drugs.

Step 2: Preclinical Research
 Before testing a drug in people, researchers must find out the toxicity of drug. The two types of
preclinical research are: In Vitro & In Vivo
1. Preclinical studies are not very large (take up to 3 years to complete)
2. Detailed information: Studies must provide dosing and toxicity levels.
3. Researchers review: findings and decide whether the drug should be tested in people After
preclinical testing
4. Gain approval for general medical use, the quality, safety and efficacy of any product must be
demonstrated.
5. Regulatory authority approval to commence clinical trials is based largely upon preclinical
pharmacological and toxicological assessment of the potential new drug in animals.
6. The U.S. Food and Drug Administration (FDA) requires: testing before the candidate drug can be
studied in humans.

The range of major tests undertaken on a potential new drug during preclinical trials.
6. Reproductive toxicity and teratogenicity
7. Mutagenicity
8. Carcinogenicity
9. Immunotoxicity
1. Pharmacokinetic profile
2. Pharmacodynamic profile
3. Bioequivalence and bioavailability
4. Acute toxicity
5. Chronic toxicity
Pharmacokinetics
a. What body does to the drug ?
b. relates to the fate of a drug in the body, particularly its
ADME.
c. Generally, ADME studies are undertaken in two species,
usually rats and dogs,
d. Repeated at various different dosage levels. Males & females.
Pharmacodynamics
a. What drug does to the body ?
b. Physiological effects
c. Drug action
d. Relationship between drug
concentration and effect

Toxicity studies
1. Toxicity studies: are carried out on all new drugs, largely via testing in animals, and the product
exhibits any short-term or long-term toxicity.
2. Acute toxicity: is usually assessed by administration of a single high dose of the test drug to rodents.
Both rats and mice (male and female) are usually employed.
3. Chronic toxicity: studies also require large numbers of animals and, in some instances, can last for
up to 2 years.
4. Administration of the drug: at three different dosage levels.
a. The highest level: toxic effect,
b. lowest level: should not induce any ill effects.
 In the USA, the FDA usually recommends a period of up to 2 years, whereas in Europe the
recommended duration is usually much shorter.

Reproductive toxicity and teratogenicity
1. All reproductive at three different dosage levels (ranging from non-toxic to slightly toxic)
2. Fertility studies: effect on male or female reproductive function.
3. The drug is administered: to males for at least 60 days (one full spermatogenesis cycle). Females are
dosed for at least 14 days before they are mated.
4. Reproductive toxicity studies: complement teratogenicity studies.
5. Teratogenicity studies: drug promotes any developmental abnormalities in the foetus. (usually rats
and rabbits)
 Bioequivalence and bioavailability
1. bioavailability relates to the proportion of a drug that actually reaches its site of action after
administration
2. Bioequivalence studies come into play if any change in product reduction/delivery systems was
being contemplated

Mutagenicity, carcinogenicity and other tests
Mutagenicity tests are usually carried out in vitro and in vivo, often using both prokaryotic and
eukaryotic organisms.
Longer-term carcinogenicity tests are undertaken if
(a)The product’s likely therapeutic indication, its administration over prolonged periods few weeks or
more .
(b)If there is any reason to suspect that the active ingredient or other constituents could be carcinogenic.
(c)biopharmaceuticals, immunotoxicity tests (product’s ability to induce an allergic or hypersensitive or
antibody response)

Step 3: Clinical Research
“Clinical research” Clinical trials are conducted to collect data regarding the safety and efficacy of
new drug and development. As the developers design the clinical study, There are several steps and
stages of approval in the clinical trials process researches send the data to the FDA for approval to
continue research and testing in humans. Once approved, human testing of experimental drugs and can
begin and is typically conducted in four phases. Each phase is considered a separate trial and, after
completion of a phase, investigators are required to submit their data for approval from the FDA before
continuing to the next phase. process are
1. Designing Clinical Trials
2. Clinical Research Phase Studies
3. The Investigational New Drug Process
4. Asking for FDAAssistance
5. FDA IND Review Team
6. Approval

Designing Clinical Trials
Researchers design clinical trials ,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:
1. Who qualifies to participate (selection criteria)
2. How many people will be part of the study
3. How long the study will last
4. Whether there will be a control group and other ways to limit research bias
5. How the drug will be given to patients and at what dosage
6. What assessments will be conducted, when, and what data will be collected
7. How the data will be reviewed and analyzed

Clinical Research Phase Studies
Phase 1
A.Study Participants: 20 to 100 healthy volunteers or people with the disease/condition.
B.Length of Study: Several months
C.Purpose: Safety and dosage
During Phase 1 studies, researchers test a new drug in normal volunteers (healthy people). In most
cases, 20 to 80 healthy volunteers or people with the disease/condition participate in Phase 1. However,
if a new drug is intended for use in cancer patients, researchers conduct Phase 1 studies in patients with
that type of cancer.
Monitored and gather information: about how a drug interacts with the human body.
Adjust dosing: Researchers adjust dosing schemes based on animal data to find out how much of a
drug the body can tolerate and what its acute side effects are.

As a Phase 1 trial continues, researchers answer research questions related to how it works in the body,
1. Side effects associated with increased dosage, and early information about how effective.
2. Administer the drug to limit risks and maximize possible benefits. This is important to the design of
Phase 2 studies.
Approximately 70% of drugs move to the next phase
Objectives:
1. Primary
a. Tolerability and safety
b. Pharmacokinetics
2. Secondary
a. Pharmacodynamics

Phase 2
Study Participants: Up to several hundred people with the disease/condition.
Length of Study: Several months to 2 years
Purpose: Efficacy and side effects
 In Phase 2 studies, researchers administer the drug to a group of patients with the disease or condition
for which the drug is being developed. Typically involving a few hundred patients, these studies aren't
large enough to show whether the drug will be beneficial.
Instead, Phase 2 studies provide researchers with additional safety data. Researchers use these data to
refine research questions, develop research methods, and design new Phase 3 research protocols.
Approximately 33% of drugs move to the next phase

Phase 3
Study Participants: 300 to 3,000 volunteers who have the disease or condition
Length of Study: 1 to 4 years
Purpose: Efficacy and monitoring of adverse reactions
Phase 3 studies provide most of the safety data. In previous studies, it is possible that less common side
effects might have gone undetected. Because these studies are larger and longer in duration, the results
are more likely to show long-term or rare side effects
Approximately 25-30% of drugs move to the next phase

Phase 4
 Study Participants: Several thousand volunteers who have the disease/condition
 Purpose: Safety and efficacy
 Phase 4 trials are carried out once the drug has been approved by FDA during the Post-Market Safety Monitoring
 Objectives:
1. Confirm the efficacy and safety in large population during practice.
2. Detect unknown/rare ADR.
3. Identification of new indication.
4. Dose refinement
A. Evaluation of new formations
B. Dosages.
C. Duration of treatment.
D. Pharmacoeconomics
E. Evaluation in different age group/types of people
F. Drug use in community
G. Quality of life assessment

The Investigational New Drug Process
Drug developers, or sponsors, must submit an IND application to FDA before beginning clinical
research, developers must include:
1. Animal study data and toxicity data
2. Manufacturing information
3. Clinical protocols (study plans)
4. Data from any prior human research
5. Information about the investigator

Asking for FDAAssistance
Drug developers are free to ask for help from FDA at any point in the drug development process,
including:
a. Pre-IND application, to review FDA guidance documents and get answers to questions that may help
enhance their research
b. After Phase 2, to obtain guidance on the design of large Phase 3 studies
c. Any time during the process, to obtain an assessment of the IND application
d. Even though FDA offers extensive technical assistance, drug developers are not required to take FDA’s
suggestions.

FDA IND Review Team
Each member has different responsibilities.
1. Project Manager: Coordinates the team’s activities throughout the review process, and is the primary contact
for the sponsor.
2. Medical Officer: Reviews all clinical study information and data before, during, and after the trial is completed.
3. Statistician: Interprets clinical trial designs and data, and works closely with the medical officer to evaluate
protocols and safety and efficacy data.
4. Pharmacologist: Reviews preclinical studies.
5. Pharmakineticist: Focuses on the drug’s ADME processes. Interprets blood-level data at different time intervals
from clinical trials, as a way to assess drug dosages and administration schedules.
6. Chemist: Analyzes how a drug was made and its stability, QC, continuity, the presence of impurities, etc.
7. Microbiologist: Reviews the data submitted, if the product is an antimicrobial product, to assess response across
different classes of microbes.

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:
Approval to begin clinical trials.
Clinical hold to delay or stop the investigation. FDA can place a clinical hold for specific reasons,
including:
Participants are exposed to significant risk.
Investigators are not qualified.
Materials for the volunteer participants are misleading.
The IND application does not include enough information about the trial’s risks.

Step 4: FDA Drug Review
 If a drug developer has evidence from its early tests and preclinical and clinical research that a
drug is safe and effective for its intended use, the company can file an application to market the
drug. The FDA review team thoroughly examines all submitted data on the drug and makes a
decision to approve or not to approve it.

New Drug Application
A New Drug Application (NDA) tells the full story of a drug. Its purpose is to demonstrate that a drug
is safe and effective for its intended use in the population studied.
A drug developer must include everything about a drug—from preclinical data to Phase 3 trial data—in
an NDA. Developers must include reports on all studies, data, and analyses. Along with clinical results,
developers must include:
1. Proposed labeling
2. Safety updates
3. Drug abuse information
4. Patent information
5. Any data from studies that may have been conducted outside the United States
6. Institutional review board compliance information
7. Directions for use

FDA Review
Once FDA receives an NDA, the review team decides if it is complete or not, the review team can
refuse to file the NDA. If it is complete, the review team has 6 to 10 months to make a decision on
whether to approve the drug. The process includes the following:
Each member of the review team conducts a full review of his or her section of the application. For
example, the medical officer and the statistician review clinical data, while a pharmacologist reviews
the data from animal studies.
FDA inspectors travel to clinical study sites to conduct a routine inspection.
The project manager assembles all individual reviews and other documents, such as the inspection
report, into an “action package.” This document becomes the record for FDA review. The review team
issues a recommendation, and a senior FDA official makes a decision.

FDAApproval
In cases where FDA determines that a drug has been shown to be safe and effective for its intended use,
it is then necessary to work with the applicant to develop and refine prescribing information. This is
referred to as “labeling.” Labeling accurately and objectively describes the basis for approval and how
best to use the drug.
Often, though, remaining issues need to be resolved before the drug can be approved for marketing.
Sometimes FDA requires the developer to address questions based on existing data. In other cases, FDA
requires additional studies. At this point, the developer can decide whether or not to continue further
development. If a developer disagrees with an FDA decision, there are mechanisms for formal appeal.

FDAAdvisory Committees
Often, the NDA contains sufficient data for FDA to determine the safety and effectiveness of a drug.
Sometimes, though, questions arise that require additional consideration. In these cases, FDA may
organize a meeting of one of its Advisory Committees to get independent, expert advice and to permit
the public to make comments. These Advisory Committees include a Patient Representative that
provides input from the patient perspective.

Step 5: FDA Post-Market Drug Safety Monitoring
Even though clinical trials provide important information on a drug’s efficacy and safety, it is
impossible to have complete information about the safety of a drug at the time of approval. Despite the
rigorous steps in the process of drug development, limitations exist. Therefore, the true picture of a
product’s safety actually evolves over the months and even years that make up a product’s lifetime in
the marketplace. FDA reviews reports of problems with prescription and over-the-counter drugs, and
can decide to add cautions to the dosage or usage information, as well as other measures for more
serious issues.
1. Supplemental Applications: Developers must file a supplemental application if they wish to make
any significant changes from the original NDA. Generally, any changes in formulation, labeling, or
dosage strength must be approved by FDA before they can be made.
2. INDs for Marketed Drugs: If sponsors want to further develop an approved drug for a new use,
dosage strength, new form, or different form or if they want to conduct other clinical research or a post-
market safety study, they would do so under an IND.

3. Manufacturer Inspections: Manufacturers may be informed of inspections in advance. The purpose
of these inspections is to make sure that developers are following GMP. FDA can shut down a facility
if minimum standards are not met.
4. Drug Advertising: All advertisements, such as product claims or reminder ads, cannot be false or
misleading. They must contain truthful information about a drug’s effectiveness, side effects, and
prescribing information.
5. Generic Drugs: This means that only the sponsor has the right to market the drug exclusively. Once
the patent expires, other drug manufacturers can develop the drug, which will be known as Generic
drugs are comparable to brand name drugs as
6. Dosage form
7. Strength
8. Safety
9. Quality
10. Intended use

Reporting Problems: FDA has several programs that allow manufacturers, health professionals, and
consumers to report problems associated with approved drugs.
Med Watch is a gateway for reporting problems with medical products and learning about new
safety information. You can subscribe to regular Med Watch safety alerts.
Medical Product Safety Network (Med Sun) monitors the safety and effectiveness of medical
devices. FDA recruits 350 healthcare providers throughout the United States to report any medical
device problems that result in serious injury or death. Each month, FDA publishes the MedSun
newsletter. The newsletter gives consumers important information about medical device safety.
Active Surveillance: Under the Sentinel Initiative, FDA is developing a new national system to more
quickly spot possible safety issues. The system will use very large existing electronic health
databases—like electronic health records systems, administrative and insurance claims databases, and
registries—to keep an eye on the safety of approved medical products in real time.

Thank you

Drug development process

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